melphalan and Adenocarcinoma

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clostridium Infections; Clostridium perfringens; Embolization, Therapeutic; Fatal Outcome; Hemolysis; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Multiple Primary; Prednisone; Sepsis

Topics: Adenocarcinoma; Aged; Colonoscopy; Gastroscopy; Humans; Male; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Prednisolone; Sigmoid Neoplasms; Stomach Neoplasms

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Castration; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Nitrogen Mustard Compounds; Prednisone; Thiotepa; Vinblastine; Vincristine

Topics: Adenocarcinoma; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Hodgkin Disease; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Melanoma; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Vincristine

Topics: Adenocarcinoma; Castration; Chlorambucil; Cobalt Isotopes; Female; Humans; Hysterectomy; Melphalan; Ovarian Neoplasms

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Division; Cyclophosphamide; Cytarabine; Female; Fluorouracil; Humans; Leukemia L1210; Leukemia, Lymphoid; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Nitrogen Mustard Compounds; Prednisone; Pregnancy; Time Factors; Trophoblastic Neoplasms; Vinblastine

Topics: Adenocarcinoma; Ascites; Carcinoma; Cyclophosphamide; Female; Fluorouracil; Humans; Injections, Intravenous; Melphalan; Nitrogen Mustard Compounds; Ovarian Neoplasms; Thiotepa

Relatively few studies have examined the activity of alkylating agents in the treatment of advanced colorectal adenocarcinoma. Recent reports have suggested possible therapeutic activity for high-dose intravenous melphalan administered with autologous bone marrow transplantation (BMT) support. We conducted a phase II study to determine the efficacy of administering intravenous melphalan at doses that do not require BMT support in patients with advanced colorectal adenocarcinoma.. Fifteen patients with histologically proven, bidimensionally measurable disease were treated. The starting dose of melphalan was 30 mg/m2, with dose escalation permitted.. No objective responses were observed. Toxic effects were primarily reversible granulocytopenia and thrombocytopenia. There were no treatment-associated deaths.. Melphalan's lack of efficacy at the doses administered does not disprove the steep chemotherapy dose-response relationship postulated for many solid tumors. However, we feel that it is unlikely that repetitive courses of high dose melphalan with autologous BMT support will be a practical approach to the management of advanced colorectal adenocarcinoma.

Topics: Adenocarcinoma; Aged; Colorectal Neoplasms; Female; Humans; Injections, Intravenous; Male; Melphalan; Middle Aged; Neoplasm Staging

The use of intravenous melphalan at higher doses is limited by severe myelosuppression. It was postulated that GM-CSF would permit the use of higher dose melphalan with only moderate myelosuppression easily manageable in an outpatient setting. Therefore, a phase I study of intravenous melphalan utilizing GM-CSF (recombinant granulocyte-macrophage colony-stimulating factor) support was initiated. Intravenous melphalan at doses of 15-45 mg/m2 was administered every 28 days. GM-CSF was utilized at doses of 10-20 micrograms/kg/day subcutaneously Days 2-21 on a 28-day cycle. Twenty-five patients received 53 courses of therapy. The dose-limiting toxicities were severe or life-threatening granulocytopenia and thrombocytopenia. Utilizing 20 micrograms/kg/day GM-CSF, the maximum tolerated dose (MTD) of melphalan is 30 mg/m2 and, with 10 mg/kg/day GM-CSF, the maximum tolerated melphalan dose is only 20 mg/m2. One patient with ovarian cancer achieved a partial response. Because the reported MTD of intravenous melphalan without GM-CSF is 30 mg/m2, GM-CSF has not allowed sufficient escalation of the intravenous melphalan dose for routine outpatient use.

Topics: Adenocarcinoma; Adult; Agranulocytosis; Anemia; Drug Evaluation; Endometrial Neoplasms; Female; Genital Neoplasms, Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leiomyosarcoma; Melphalan; Ovarian Neoplasms; Recombinant Proteins; Thrombocytopenia

This prospective randomized study in nonhormonally responsive adenocarcinoma of the prostate shows that response rates to melphalan vs cyclophosphamide groups were virtually identical.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Fluorouracil; Humans; Male; Melphalan; Methotrexate; Prednisone; Prostatic Neoplasms; Random Allocation; Vincristine

The combinations of triethylenethiophosphoramide and methotrexate (TM) and cyclophosphamide, Adriamycin (doxorubicin), and 5-fluorouracil (CAF) were compared, both as sequential and fixed rotational treatments for advanced ovarian cancer, with L-phenylalanine mustard (L-PAM). Treatment with CAF produced a higher response rate (25% complete responses plus 31% partial responses) than treatment with L-PAM (15% complete responses plus 18% partial responses). A fixed rotation of TM and CAF resulted in longer survival (median of 15 months and 75th percentile of 27 months) than sequential treatment with TM initially, followed by CAF upon failure (median of 12 months and 75th percentile of 22 months). The fixed rotation of TM and CAF also increased progression-free survival (median of 12 months and 75th percentile of 24 months) over that achieved by initial treatment with TM (median of 6 months and 75th percentile of 15 months) or L-PAM (median of 9 months and 75th percentile of 21 months). Most patients (96%) on the fixed rotation were treated with both TM and CAF. Fewer patients (62%) on the sequential schedule with TM actually received both combination regimens, and even fewer patients (37%) beginning on CAF ever crossed over to TM. Patient age of 50 years or younger was a favorable prognostic factor for response, survival, and time to first treatment failure (progression-free survival). Disease Stage IIIA or IIIB, surgery including a bilateral salpingo-oophorectomy plus hysterectomy, and treatment within 6 months of initial diagnosis were favorable predictors for both survival and time to first treatment failure. Ambulatory performance status and well-differentiated disease were favorable prognostic factors for survival. Patients with unevaluable disease failed later than those with evaluable disease who, in turn, failed later than patients with measurable disease.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms; Prospective Studies; Random Allocation; Thiotepa

A prospective randomized study was conducted in women with suboptimal (greater than or equal to 3 cm residual) Stage III, Stage IV, and recurrent ovarian adenocarcinoma to determine if combination chemotherapy is more effective than melphalan alone in achieving remission and improving survival. Of 233 evaluable patients with measurable disease, there were 64 treated with melphalan alone, of whom 20% achieved a clinical complete response and 17%, a partial response. Of the 97 patients receiving melphalan plus hexamethylmelamine, 28% achieved complete response compared with 32% of 72 patients given Adriamycin plus cyclophosphamide. The partial response rates for the combinations were 24% and 17%, respectively. The effect of these treatments was assessed in an additional 136 evaluable patients without measurable disease by progression-free interval and duration of survival. After statistically adjusting for distribution of cell type and grade, the clinical complete response rate for Adriamycin and cyclophosphamide (32%) in measurable cases was significantly higher (P = 0.04) than for melphalan alone. However, this combination did not improve median survival (12.3, 13.5, and 14.2 months, respectively, for M, M + H, and A + C). None of the other parameters showed a statistically significant advantage for combination chemotherapy, but the combinations caused more hematologic and gastrointestinal toxicity.

Topics: Adenocarcinoma; Adult; Aged; Altretamine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Prognosis; Random Allocation; Triazines

Eighty patients with advanced ovarian adenocarcinoma were treated in a prospective, randomized trial comparing a four-drug combination--hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil--with the oral alkylating agent, melphalan. Treatment with the four-drug combination was associated with a significantly increased overall response rate (75 vs. 54 per cent) (P less than 0.05), more complete remissions (33 vs. 16 per cent) and longer median survival (29 vs. 17 months) (P less than 0.02) but more severe toxicity than occurred with melphalan. Patients with minimal residual disease had a significantly higher overall response rate than patients with extensive residual disease (84 vs. 53 per cent) (P less than 0.05). Patients with advanced disease who achieved a complete remission documented by peritoneoscopy or laparotomy (or both) have a median survival that will exceed three years. The four-drug regimen is more effective than melphalan in the management of advanced ovarian adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Altretamine; Antineoplastic Agents; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms; Prospective Studies

Topics: Adenocarcinoma; Clinical Trials as Topic; Colonic Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Melphalan; Middle Aged; Rectal Neoplasms

In an attempt to improve the response rate and hopefully the survival rate in women with advanced ovarian adenocarcinoma, three new modalities of therapy for ovarian adenocarcinoma were undertaken in 97 women. Sequential therapy consisted of surgery followed by chemotherapy, second-look laparotomy, and subsequent whole abdominal radiation. Eight women exhibiting a complete clinical response to chemotherapy were subjected to this treatment. However, only one woman (12%) is surviving without evidence of tumor recurrence. Concomitant therapy consisted of external radiation and single alkylating agent chemotherapy in 23 women. Again, the survival was poor: a 5-year survival of 8% without tumor recurrence. The third treatment modality consisted of a randomized study of 66 patients in whom single agent therapy with melphalan was compared with multiple agent therapy consisting of cyclophosphamide, dactinomycin, and 5-fluorouracil. In those women with stage III and IV serous adenocarcinoma of the ovary, a 63% response rate was obtained in patients receiving triple chemotherapy as compared to a 45% response rate in those receiving melphalan. Moreover, 40% of the group given triple chemotherapy exhibited a complete response as compared to only 18% in the group given melphalan.

Topics: Adenocarcinoma; Alkylating Agents; Chlorambucil; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms; Thiotepa

The therapeutic effects of adriamycin and of melphalan in patients with advanced carcinoma of the ovary were tested in a prospective randomized study. Complete and partial remission occurred in eight of 19 patients treated with adriamycin and in four of 20 patients given melphalan. The difference, however, is not statistically significant. The median duration of complete and partial remissions was slightly longer after treatment with melphalan than with adriamycin. The number of cycles required to produce the initial regression state was less in the patients in the group given adriamycin as compared with those in the group treated with melphalan. No cross resistance was observed between the two drugs. These data indicate that, in patients with carcinoma of the ovary, the therapeutic efficacy of adriamycin is competitive with that of the most effective conventional agents, such as melphalan.

Topics: Adenocarcinoma; Carcinoma; Clinical Trials as Topic; Doxorubicin; Drug Evaluation; Endometriosis; Female; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms; Remission, Spontaneous

Twenty-four fully staged, previously untreated patients with advanced ovarian carcinoma were prospectively randomized to either intensive intravenous cyclophosphamide or conventional oral Melphalan therapy. The median durations of initial remissions (5 and 6 mo) and the median durations of survival (15 and 14 mo) were similar for the two regimens but the toxicity of the intensive regimen was excessive. Followup indicates that long term disease free survivals are possible in those patients who achieve complete remissions on chemotherapy alone as three of the four patients achieving complete remission in the present study remain free of disease with a median survival in excess of 30 mo. High dose intensive alkylating agent therapy in the manner used in the present study fails to enhance the response to chemotherapy and produces unacceptable toxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Administration, Oral; Cyclophosphamide; Cystadenocarcinoma; Dose-Response Relationship, Drug; Female; Humans; Injections, Intravenous; Laparoscopy; Melphalan; Ovarian Neoplasms; Remission, Spontaneous; United States

To improve the therapeutic properties of the antitumor agent Sarcolysin, we have previously developed and characterized a dosage form representing its ester conjugate with decanol embedded in ultra-small phospholipid nanoparticles less than 30 nm in size ("Sarcolysin-NP"). The effect of the resulting composition was investigated in vivo in comparison with the free substance of sarcolysin. The composition intravenous administration to mice showed an improvement in the pharmacokinetic parameters of sarcolysin associated with its initial higher (by 22%) level in the blood and prolonged circulation, which was also observed in mice with P388 tumor. In mice with three types of tumors - lymphocytic leukemia P388, lymphocytic leukemia L1210, and adenocarcinoma of the mammary gland Ca755 - administration of two doses of sarcolysin over a period of 7 days showed its predominant antitumor effect. The maximum tumor growth inhibition was noted for lymphocytic leukemia L1210 and adenocarcinoma of the mouse mammary gland Ca755 (at a dose of Sarcolysin-NP - 8,4 mg/kg), which was higher in comparison with free substance by more than 24% and 17%, respectively. Differences in the life span of the treated animals were revealed significantly at a dose of 10 mg/kg and amounted to 25% and 17,4% for lymphocytic leukemia P388 and L1210, respectively, and 11% for adenocarcinoma Ca755. In an experiment on rats, acute toxicity of Sarcolysin-NP administered intravenously showed that an average LD50 value 2-3 times exceeded a similar parameter for commercial preparations of free sarcolysin (Melphalan and Alkeran), which indicates its lower toxicity.. S tsel'iu uluchsheniia terapevticheskikh svoĭstv protivoopukholevogo agenta sarkolizina ranee nami byla razrabotana i okharakterizovana lekarstvennaia forma, predstavliaiushchaia soboĭ ego slozhnoéfirnyĭ kon"iugat s dekanolom, vstroennyĭ v ul'tramalye fosfolipidnye nanochastitsy menee 30 nm (Sarkolizin-NF). V rabote issledovali deĭstvie étoĭ kompozitsii v usloviiakh in vivo v sravnenii so svobodnoĭ substantsieĭ sarkolizina. Pri vnutrivennom vvedenii ee mysham bylo pokazano uluchshenie farmakokineticheskikh parametrov sarkolizina, sviazannykh s bol'shim (na 22%) ego pervonachal'nym urovnem v krovi i s prolongirovannoĭ tsirkuliatsieĭ, chto nabliudalos', v tom chisle, na myshakh s opukhol'iu R388. Pri étom kolichestvo i dlitel'nost' nakhozhdeniia sarkolizina v tkani opukholi byli sushchestvenno vyshe (bolee chem v dva raza) po sravneniiu so svobodnoĭ substantsieĭ. Na myshakh s tremia vidami opukholeĭ (limfoleĭkoz P388, limfoleĭkoz L1210 i adenokartsinoma molochnoĭ zhelezy Ca755) pokazano preimushchestvennoe protivoopukholevoe deĭstvie, proiavliavsheesia v dostoverno bol'shem tormozhenii rosta opukholeĭ i uvelichenii prodolzhitel'nosti zhizni zhivotnykh. Maksimal'noe tormozhenie rosta opukholi pri lechenii Sarkolizinom-NF v doze 8,4 mg/kg otmecheno dlia limfoleĭkoza L1210 i adenokartsinomy molochnoĭ zhelezy mysheĭ Ca755 (v sravnenii s substantsieĭ vyshe bolee chem na 24% i 17% sootvetstvenno). Pri doze preparata 10 mg/kg razlichiia v prodolzhitel'nosti zhizni zhivotnykh byli vyiavleny dostoverno i sostavili 25% i 17,4% dlia limfoleĭkozov R388 i L1210 sootvetstvenno i 11% dlia adenokartsinomy Ca755. Pri vnutrivennom vvedenii krysam ostraia toksichnost' Sarkolizina-NF (znachenie LD50) byla v 2-3 raza nizhe, chem LD50 dlia kommercheskikh preparatov svobodnogo sarkolizina (Melfalana i Alkerana), chto svidetel'stvuet o men'sheĭ toksichnosti preparata Sarkolizin-NF.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Melphalan; Mice; Nanoparticles; Phospholipids; Rats

Sinonasal intestinal-type adenocarcinomas (SNS-ITAC) are very rare tumors that resemble colorectal cancer in many of their pathological and molecular characteristics. Indeed, in most published series, 10%-14% of SNS-ITAC harbor mutations in

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cetuximab; Cytarabine; ErbB Receptors; Etoposide; Genotype; Humans; Intestinal Neoplasms; Liquid Biopsy; Male; Melphalan; Paranasal Sinus Neoplasms

The aim of this study was to determine the efficacy of 252Californium neutron intracavitary brachytherapy using a two-channel Y applicator combined with external beam radiotherapy for the treatment of endometrial cancer.. Thirty-one patients with stage I-III endometrial cancer were recruited for this study. The stage I patients received only 252Californium neutron intracavitary brachytherapy with a two-channel applicator. The stage II and III patients received both 252Californium neutron intracavitary brachytherapy using a two-channel applicator and parallel-opposed whole pelvic radiotherapy.. The five-year local control rate was 80.6% (25/31), the overall survival rate was 51.6% (16/31), and the disease-free survival rate was 54.8% (17/31). The incidence of serious late complications was 12.9% (4/31).. 252Californium neutron intracavitary brachytherapy using a two-channel applicator combined with external beam radiotherapy was effective for treating endometrial cancer and the incidence of serious late complications related to this combination was within an acceptable range.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Californium; Carmustine; Combined Modality Therapy; Cytarabine; Endometrial Neoplasms; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Podophyllotoxin; Survival Rate; Treatment Outcome

Cyclooxygenase (COX)-2 plays an important role in tumorigenesis and has been implicated to be a critical factor for invasion and metastasis of lung cancer. Tetramethylpyrazine (TMP), an effective component of the traditional Chinese medicine Chuanxiong, has been traditionally used in treating neurovascular and cardiovascular diseases. Recently TMP has been reported to have beneficial effect in cancer patients. However, the function and the mechanism of TMP in lung cancer have not been elucidated to date. In this study, we investigated the in vitro and in vivo effect of TMP in tumorigenesis and whether COX-2 is a molecular target of TMP. We showed that TMP exhibited a dose- and time-dependent inhibition on A549 cell proliferation by suppressing cell cycle progression. In vitro treatment of A549 cells with TMP resulted in a significant inhibition of invasion, associated with reduced activities of COX-2 and MMP-2/TIMP-2. Furthermore, in vivo experiments showed that TMP significantly suppressed metastatic growth of A549 cells and COX-2 expression in metastatic nude mouse model. This preclinical study provides the first evidence for the novel anti-tumor effects of TMP as a COX-2 pathway inhibitor in human adenocarcinoma cell line A549. These studies suggest that TMP may serve as an effective agent for the treatment and chemoprevention of non-small cell lung cancer.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 2 Inhibitors; Dinoprostone; Female; Humans; Immunoglobulin G; Lung Neoplasms; Matrix Metalloproteinase 2; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Pyrazines; Xenograft Model Antitumor Assays

In order to determine the applicability of oxaliplatin in isolated liver perfusion, we identified the interaction between combinations of oxaliplatin and melphalan in 13 human colorectal cancer cell lines.. Cytotoxic activity was determined by the MTT-assay. Three different administration schedules of the two drugs were compared and median effect isobologram analysis was applied to the results, to determine the presence of synergism, additive effects, or antagonism as described by Chou and Talalay.. Resistance to melphalan did not correspond to resistance to oxaliplatin. All combinations of melphalan and oxaliplatin showed synergistic or additive interaction in the majority of the cell lines. One hour of oxaliplatin followed by 1h of melphalan showed the lowest percentage of cell viability, with synergy in 10 out of 13 cell lines at 50% cell viability. Simultaneous treatment showed the highest cell viability, with antagonism in six cell lines, additivity in two cell lines, synergism in five cell lines at 50% cell viability. One hour of melphalan followed by 1h of oxaliplatin showed synergy in six cell lines, antagonism in another six, and additivity in one cell line.. Our findings suggest a schedule-dependent synergistic interaction between melphalan and oxaliplatin. Therefore, oxaliplatin should be considered as a new, potentially valuable additional agent to the currently commonly used melphalan in isolated hepatic perfusion in colorectal cancer patients.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Drug Administration Schedule; Drug Interactions; Drug Resistance, Neoplasm; Drug Synergism; Drug Therapy, Combination; Humans; In Vitro Techniques; Melphalan; Organoplatinum Compounds; Oxaliplatin; Time Factors

Topics: Adenocarcinoma; Animals; Autophagy; Cell Line, Tumor; Cell Proliferation; Chloroquine; Humans; Immunoglobulin G; Macrolides; Melphalan; Mice; Oxidative Phosphorylation; Pancreatic Neoplasms; Reactive Oxygen Species; Xenograft Model Antitumor Assays

Treatment of tumor-bearing mice with mouse (m)TNF-alpha, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-alpha and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Alkylating; CD4-Positive T-Lymphocytes; Colonic Neoplasms; Combined Modality Therapy; Drug Delivery Systems; Drug Screening Assays, Antitumor; Fibrosarcoma; Immunoconjugates; Immunoglobulin Fragments; Immunologic Memory; Lymphocyte Activation; Lymphocyte Depletion; Lymphocytes, Tumor-Infiltrating; Melphalan; Mice; Mice, Inbred BALB C; Mice, SCID; Neovascularization, Pathologic; T-Lymphocytes, Cytotoxic; Tumor Necrosis Factor-alpha; Vaccination

Isolated lung perfusion is an experimental technique for the treatment of lung metastases. Single-agent isolated lung perfusion does not result in complete remission. We studied the in vivo and in vitro efficacy of combinations of gemcitabine, cisplatin, and melphalan.. In vitro, using the sulforhodamine B assay, CC531s cells were incubated with cisplatin, gemcitabine, or melphalan or with a combination of these drugs. One drug was added at concentrations causing 25% growth inhibition, whereas the second drug was added at variable concentrations. In vivo, left pulmonary metastases were induced in Wag/Rij rats by means of intravenous injection of CC531s adenocarcinoma cells. At day 7, rats underwent left isolated lung perfusion with gemcitabine (n = 7), cisplatin (n = 9), melphalan (n = 7), gemcitabine-cisplatin (n = 6), melphalan-gemcitabine (n = 6), and cisplatin-melphalan (n = 7). Death by means of metastatic disease was the end point. Survival and differences in survival were assessed by using Kaplan-Meier and log-rank testing.. In vitro synergistic activity was observed for melphalan-gemcitabine, whereas other combinations showed additive or antagonistic activity. In vivo treated rats lived longer compared with control animals ( P < .0001). In isolated lung perfusion melphalan resulted in longer survival compared with gemcitabine ( P = .0016) and cisplatin ( P = .046). Isolated lung perfusion with melphalan-gemcitabine resulted in 67% survival of the rats after 90 days versus 0% in other groups.. Isolated lung perfusion monotherapy or combination therapy with gemcitabine, cisplatin, or melphalan resulted in significantly longer survival compared with that seen in control animals. Isolated lung perfusion combination therapy with melphalan-gemcitabine resulted in the best survival either in vitro or in vivo.

Topics: Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Colorectal Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Gemcitabine; In Vitro Techniques; Inhibitory Concentration 50; Lung Neoplasms; Male; Melphalan; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

Isolated hepatic perfusion has been used in patients with colorectal cancer (CRC) metastatic to the liver. We sought to determine whether perfusion with antisense oligodeoxynucleotides results in the downregulation of beta-catenin and whether this improves tumor response to isolated limb perfusion (ILP) in a heterotopic model of human CRC.. Adenomatous polyposis coli-mutant human CRC xenografts were implanted into athymic rats. Animals were randomized to the following groups: (1) no treatment, (2) control ILP, (3) melphalan ILP, (4) ILP with antisense specific for beta-catenin, (5) ILP with nonspecific antisense, and (6) melphalan plus beta-catenin-specific antisense ILP. Tumor response and Western blot analysis of protein expression were evaluated.. The maximal decrease (mean +/- SE) in tumor volume was 0% +/- 10% for no treatment, 19% +/- 14% for control ILP, 58% +/- 3% for melphalan ILP, 58% +/- 9% for beta-catenin-specific ILP, 13% +/- 19% for nonspecific antisense ILP, and 73% +/- 6% for melphalan plus beta-catenin-specific ILP (P < .05 for melphalan ILP, beta-catenin-specific ILP, and melphalan plus antisense ILP). Tumor regrowth was delayed for 6 days after control ILP, 24 days after melphalan ILP, 20 days after beta-catenin-specific ILP, 10 days after nonspecific antisense ILP, and 60 days after melphalan plus beta-catenin-specific ILP (P < .05 for melphalan plus beta-catenin-specific ILP compared with all others). Western blotting revealed prolonged suppression of beta-catenin expression after beta-catenin-specific ILP.. Short-term beta-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC.

Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Animals; Antineoplastic Agents, Alkylating; beta Catenin; Cell Line, Tumor; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Extremities; Female; Genetic Therapy; Melphalan; Models, Animal; Oligodeoxyribonucleotides, Antisense; Rats; Remission Induction

Primary hepatocellular carcinoma is one of the most common malignancies worldwide. Isolated hepatic perfusion (IHP) is a regional treatment technique that isolates the organ to allow delivery of high-dose chemotherapy, biological agents, and hyperthermia directly to unresectable cancers confined to the liver. This study presents our experience using IHP with melphalan with or without tumor necrosis factor (TNF) to treat patients with hepatocellular carcinoma or adenocarcinoma of hepatobiliary origin. Nine patients with unresectable primary hepatic malignancies underwent a 60-minute IHP with 1.5 mg/kg melphalan with or without 1.0 mg TNF. Four patients failed one or more previous treatment regimens, and the mean hepatic replacement by tumor was 41% (range 10% to 75%). Patients were monitored for response, toxicity, time to recurrence, and survival. Six (67%) of nine patients experienced greater than 50% regression of tumor by objective radiographic imaging and an additional patient had a 45% reduction in tumor burden. Mean time to progression was 7.7 months for those who responded to treatment. Patients who had a response to therapy had an average overall survival of 16.3 months. IHP can be performed safely and has significant antitumor activity in patients with unresectable primary hepatic malignancies. Hepatic progression continues to be the dominant factor influencing survival in this group of patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Liver Neoplasms; Male; Melphalan; Middle Aged; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

Increasing the drug concentration in tumors may produce massive tumoral response. By using a variety of hepatic vascular isolation techniques, high concentrations of chemotherapeutic drugs may be achieved in the hepatic vascular bed.. Complete percutaneous isolated hepatic perfusion (IHP) is feasible and safe.. Case series.. The hepatobiliary unit of a university hospital.. Ten patients with irresectable and chemoresistant hepatic tumors were eligible for study participation; 4 patients with hepatic metastases of breast cancer, gastric cancer, colorectal cancer, and cholangiocarcinoma were included.. Patients received 3 successive courses of chemotherapy by IHP. The first course was given at laparotomy, and the next 2 courses were given percutaneously. The interval between courses was 3 to 6 weeks. Each course involved IHP of the liver for 15 to 30 minutes, without oxygenation, with 1 to 3 boluses of melphalan (15 mg).. Morbidity and mortality.. Ten IHPs were performed (4 at laparotomy and 6 percutaneously). Concentrations of melphalan in the extracorporeal circulation were 10 times higher than those in the systemic circulation. Percutaneous IHPs had more leakage than those at laparotomy. However, hepatotoxicity was minimized. One patient experienced hepatic artery thrombosis, and 3 had severe neutropenia. Minor complications included ascites and pleural effusion. No deaths were observed 2 months after the last IHP. One partial response was observed (hepatic metastases of breast cancer).. Percutaneous IHP for intensive chemotherapy is less aggressive and less hepatotoxic than IHP at laparotomy and may be iterative.

Topics: Adenocarcinoma; Antineoplastic Agents; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Cholangiocarcinoma; Colorectal Neoplasms; Fatal Outcome; Female; Humans; Laparotomy; Liver Neoplasms; Male; Melphalan; Middle Aged; Radiography, Interventional; Stomach Neoplasms

We sought to enhance the selective toxicity of tumor necrosis factor alpha (TNFalpha) to permit its systemic use in cancer therapy. Because ligand-targeted therapeutics have proven successful in improving the selective toxicity of drugs, we prepared a fusion protein (L19mTNFalpha) composed of mouse TNFalpha and a high-affinity antibody fragment (L19 scFv) to the extradomain B (ED-B) domain of fibronectin, a marker of angiogenesis. L19mTNFalpha was expressed in mammalian cells, purified, and characterized. L19mTNFalpha was an immunoreactive and biologically active homotrimer. Radiolabeled L19mTNFalpha selectively targeted tumor neovasculature in tumor-bearing mice, where it accumulated selectively and persistently (tumor-to-blood ratio of the percentage of injected dose per gram [%ID/g] of 700, 48 hours from injection). L19mTNFalpha showed a greater anticancer therapeutic activity than both mTNFalpha and TN11mTNFalpha, a control fusion protein in which an antibody fragment, irrelevant in the tumor model used, substituted for L19. This activity was further dramatically enhanced by its combination with melphalan or the recently reported fusion protein L19-IL2. In conclusion, L19mTNFalpha allows concentrating therapeutically active doses of TNFalpha at the tumor level, thus opening new possibilities for the systemic use of TNFalpha in cancer therapy.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Animals; Antigen-Antibody Reactions; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Screening Assays, Antitumor; Drug Synergism; Fibronectins; Immunoglobulin Fragments; Injections, Intravenous; Interleukin-2; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neovascularization, Pathologic; Recombinant Fusion Proteins; Subcutaneous Tissue; Teratocarcinoma; Transfection; Tumor Necrosis Factor-alpha

Isolated lung perfusion (ILuP) with melphalan (MN) is superior to intravenous infusion for the treatment of pulmonary carcinoma and sarcoma metastases. However, it is unknown whether a bolus injection of MN into the perfusion circuit or ILuP with a fixed concentration of MN will result in the highest lung levels.. ILuP with 0.5 mg MN was performed in Wag-Rij rats for 30 minutes either by a single-pass system (SP) (fixed concentration) (n = 10) or by reperfusion (RP) (bolus injection) (n = 10). In a separate experiment, rats were perfused with blood as the perfusate. In a third experiment, tumor levels were compared between SP, RP, or intravenous therapy with a dose of 0.5 mg. For induction of pulmonary metastases, 0.5 x 10(6) single adenocarcinoma cells were injected intravenously and therapy was given on day 30. For comparison of drug concentrations, unpaired Student's t test was applied. Statistical significance was accepted at p less than 0.05.. Lung perfusion studies were succesfully performed without systemic leakage. Temperature of perfusate and rats was 34 degrees C to 37 degrees C. A significantly higher hematocrit (mean 27.9) compared with buffered starch (mean 2.5) did not result in higher MN lung levels or lower wet-to-dry ratio. Tumor levels were significantly higher after ILuP compared with intravenous therapy. However, no difference in tumor and lung levels was seen between single-pass and reperfusion.. Both ILuP techniques resulted in significantly higher MN lung levels than after intravenous therapy. Because no difference was seen between single-pass and recirculating perfusion, MN can be injected as a bolus into the closed perfusion circuit.

Topics: Adenocarcinoma; Animals; Biological Availability; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Infusions, Intra-Arterial; Infusions, Intravenous; Lung; Lung Neoplasms; Male; Melphalan; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

The overexpression of lectins by malignant cells compared with normal ones can be used for the targeting of drug-loaded liposomes to tumours with the help of specific carbohydrate ligands (vectors). Recently we have shown that liposomes bearing specific lipid-anchored glycoconjugates on a polymeric matrix bind in vitro to human malignant cells more effectively and, being loaded with a lipophilic prodrug of merphalan, reveal higher cytotoxic activity compared with unvectored liposomes. In this study, carbohydrate-equipped cytotoxic liposomes were tested in vivo in a mouse breast cancer model, BLRB-Rb (8.17)1Iem strain with a high incidence of spontaneous mammary adenocarcinoma (SMA). Firstly, a cell line of the SMA was established which was then used to determine the specificity of the tumour cell lectins. After screening of the lectin specificity of a number of fluorescent carbohydrate probes, SiaLe(X) was shown to be the ligand with the most affinity, and a lipophilic vector bearing this saccharide was synthesised. Then different liposomal formulations of the synthetic merphalan lipid derivative and SiaLe(X) vector were prepared and applied in the treatment of mice with grafted adenocarcinomas. The results of the tumorigenesis data show that the therapeutic efficacy of merphalan increases sharply after its insertion as a lipophilic prodrug into the membrane of SiaLe(X)-vectored liposomes.

Topics: Adenocarcinoma; Animals; Drug Screening Assays, Antitumor; Female; Ligands; Liposomes; Mammary Neoplasms, Experimental; Melphalan; Mice; Selectins; Tumor Cells, Cultured

Isolated perfusion of the extremities with high-dose tumour necrosis factor alpha (TNF-alpha) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-alpha and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 microg TNF-alpha. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-alpha and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-alpha alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-alpha, the minimal threshold concentration of TNF-alpha to exert its anti-tumour effects was not reached. The applicability of TNF-alpha in isolated kidney perfusion for human tumours seems, therefore, questionable.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Kidney; Male; Melphalan; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Rats; Renal Insufficiency; Shock, Septic; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Survival after isolated lung perfusion (ILuP) with melphalan was tested in a model of unilateral pulmonary adenocarcinoma.. On day 0, rats were randomized into four groups: Group 1 (n = 9) received tumor cells intravenously for induction of bilateral lung metastases, whereas groups 2-4 (n = 21) underwent a 10-min occlusion of the right pulmonary artery during tumor cell injection for induction of unilateral left lung metastases. On day 7, groups 1 and 2 received no treatment. Group 3 underwent left ILuP with melphalan (2.0 mg/kg) while group 4 received melphalan intravenously (0.5 mg/kg). The end point of the study was death from metastatic disease.. Median survival of ILuP-treated animals (81 +/- 12 days) was significantly longer compared to group 1 (18 +/- 1 days; p = 0.0001), group 2 (28 +/- 3 days; p = 0.0002) and group 4 (37 +/- 6; p = 0.0004).. ILuP with melphalan prolongs survival in the treatment of experimental metastatic pulmonary carcinoma.

Topics: Adenocarcinoma; Animals; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Lung Neoplasms; Male; Melphalan; Neoplasm Transplantation; Pilot Projects; Rats; Rats, Inbred Strains; Survival Rate

Melphalan was investigated for antitumoral activity using two schedules of exposure (solid versus sequential exposure) in two human cancer cell lines (8226 and A2780). Sequential exposure of melphalan was more effective than solid exposure at the same total dose. The IC50 values averaged 8.2 (solid exposure) and 0.16 microgram/ml (sequential exposure) for 8226 cells (myeloma), and 7.5 (solid) and 0.53 microgram/ml (sequential) for A2780 cells (ovarian carcinoma). Intracellular melphalan accumulation, determined by high-performance liquid chromatography, showed that the area under the intracellular concentration of melphalan versus time curve (between 0 and 30 h) was significantly higher after sequential doses (9.4 micrograms/ml x h) than after solid dose (6.6 micrograms/ml x h). Moreover, intracellular/extracellular concentration ratios indicated that melphalan uptake followed a passive transport system. The increase of both duration of exposure (11 h after solid exposure versus 20 h after sequential doses) and intracellular concentrations 5-6 h after the beginning of the experiment (approximately 3 times higher after sequential doses) indicate sequential administration of melphalan could be more effective than solid exposure.

Topics: Adenocarcinoma; Antineoplastic Agents, Alkylating; Cell Count; Cell Survival; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Humans; Melphalan; Ovarian Neoplasms; Tumor Cells, Cultured

Loss of DNA mismatch repair is a common finding in hereditary non-polyposis colon cancer as well as in many types of sporadic human tumours. We compared the effect of loss of DNA mismatch repair on drug sensitivity as measured by a clonogenic assay with its effect on the ability of the same drug to enrich for mismatch repair-deficient cells in a proliferating tumour cell population. Mixed populations containing 50% DNA mismatch repair-deficient cells constitutively expressing green fluorescent protein and 50% mismatch repair-proficient cells were exposed to different chemotherapeutic agents. 6-Thioguanine, to which DNA mismatch repair-deficient cells are known to be resistant, was included as a control. The results in the cytotoxicity assays and in the enrichment experiments were concordant. Treatment with either carboplatin, cisplatin, doxorubicin, etoposide or 6-thioguanine resulted in enrichment for mismatch repair-deficient cells, and clonogenic assays demonstrated resistance to these agents, which varied from 1.3- to 4.8-fold. Treatment with melphalan, paclitaxel, perfosfamide or tamoxifen failed to enrich for mismatch repair-deficient cells, and no change in sensitivity to these agents was detected in the clonogenic assays. These results identify the topoisomerase II inhibitors etoposide and doxorubicin as additional agents for which loss of DNA mismatch repair causes drug resistance. The concordance of the results from the two assay systems validates the enrichment assay as a rapid and reliable method for screening for the effect of loss of DNA mismatch repair on sensitivity to additional drugs.

Topics: Adenocarcinoma; Antineoplastic Agents; Carboplatin; Cell Separation; Cisplatin; Colorectal Neoplasms; Cyclophosphamide; DNA Repair; DNA, Neoplasm; Doxorubicin; Enzyme Inhibitors; Etoposide; Humans; Melphalan; Paclitaxel; Tamoxifen; Thioguanine; Tumor Cells, Cultured; Tumor Stem Cell Assay

The overexpression of lectins by malignant cells was applied for in vitro targeting of liposomes equipped with a saccharide vector and loaded in the lipid phase with a lipid derivative of anticancer agent sarcolysine. The lectin specificity of human leukemia HL-60 and human lung adenocarcinoma ACL cells was revealed by tests with fluorescein-labeled sugar probes. With the help of fluorescent lipid dye it was shown that active saccharide ligands increased the level of the vectored liposome binding to malignant cells by 50-80% as compared to liposomes without vector or with inactive one. The degree of liposome/cell membrane fusion was monitored fluorometrically and was shown to be complete and independent of the vectors. The targeted drug-loaded liposomes had the cytotoxic activity 2-4 times higher as compared to the vector-free ones.

Topics: Acrylic Resins; Adenocarcinoma; Antigens, Tumor-Associated, Carbohydrate; Carbohydrate Sequence; Cell Membrane; Diglycerides; Drug Carriers; Fluorescein; HL-60 Cells; Humans; Liposomes; Melphalan; Molecular Sequence Data; Oligosaccharides; Rhodamines; Tumor Cells, Cultured

Isolated left lung perfusion with melphalan and human tumor necrosis factor-alpha for pulmonary metastatic adenocarcinoma in the WAG/Rij rat was studied.. Survival was determined for melphalan, human tumor necrosis-alpha. Lung, pulmonary effluent, and serum melphalan were analyzed by chromatography after isolated lung perfusion or intravenous injection. On day 0, rats were injected with 2.0 x 10(6) CC531S cells intravenously. On day 7, rats underwent sham thoracotomy, received melphalan intravenously, or underwent isolated left lung perfusion with saline, melphalan, tumor necrosis factor, and a combination of the latter two. On day 14, tumor nodules were counted.. For the doses of 400 microg tumor necrosis factor, 1,000 microg tumor necrosis factor, or both melphalan and tumor necrosis factor (2 mg + 200 microg), survival rates after contralateral pneumonectomy were 33%, 17%, and 80%, respectively. Survival in all other groups was 100%. Left lung melphalan level was significantly higher after isolated lung perfusion compared to intravenous administration. Significantly fewer left lung nodules were found for 0.5 mg isolated lung perfusion with melphalan (28+/-17) compared to isolated administration (200+/-0) (p = 0.001), and for 1.0 mg intravenous lung perfusion with melphalan (16+/-10) compared to controls (171+/-65) (p = 0.00047). Tumor necrosis factor showed no significant effect.. Isolated lung perfusion with melphalan is an effective treatment for pulmonary metastases from adenocarcinoma in the rat.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Injections, Intravenous; Lung Neoplasms; Male; Melphalan; Pneumonectomy; Rats; Tumor Necrosis Factor-alpha

Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Antineoplastic Agents; Carboplatin; Carrier Proteins; Cisplatin; Colorectal Neoplasms; Cyclophosphamide; DNA Adducts; DNA Damage; DNA Repair; DNA-Binding Proteins; DNA, Neoplasm; Doxorubicin; Drug Resistance, Neoplasm; Endometrial Neoplasms; Etoposide; Female; Fluorouracil; Humans; Melphalan; Methylnitronitrosoguanidine; Mutagenesis; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins; Nuclear Proteins; Paclitaxel; Proto-Oncogene Proteins; Thioguanine; Tumor Cells, Cultured

Human breast carcinoma (MCF7-MLNr) cells resistant to the bifunctional drugs L-phenylalanine mustard (L-PAM, 5-fold resistance), mechlorethamine (9-fold), cisplatin (3-fold), and BCNU (3-fold) were used to investigate the role of DNA repair in the development of resistance to alkylating agents. We have previously shown that neither L-PAM transport and metabolism nor glutathione-associated enzymes were altered in MCF7-MLNr cells, compared to the sensitive cells MCF7-WT. This study shows that treatment of pRSV-CAT plasmid with L-PAM at concentrations up to 1 microM proportionally inhibit the expression of chloramphenicol acetyl transferase (CAT) activity, while higher concentrations abolished CAT activity. pRSV-CAT reactivation was significantly increased when plasmid was transfected into MCF7-MLNr cells, compared to MCF7-WT cells. This indicates that resistant cells have more efficient capacity to recognize and repair L-PAM induced DNA damage. The mRNA expression of DNA nucleotide excision repair genes ERCC1, XPD (ERCC2), XPB (ERCC3), and polymerase beta was found to be similar in both the MCF7-WT and MCF7-MLNr cells. Western blot analysis also reveals no difference in the expression of ERCC1, AP endonuclease, poly (ADP-ribose) polymerase, and alkyl-N-purine-DNA glycosylase proteins. The lack of correlation between enhanced host cell reactivation capacity in resistant cells, and the expression of these specific DNA repair genes suggests that proteins encoded by these genes are not rate limiting steps for resistance to bi-functional alkylating drugs in human breast cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents, Alkylating; Blotting, Northern; Blotting, Western; Breast Neoplasms; DNA Repair; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Melphalan; Plasmids; Tumor Cells, Cultured

A2780 and COLO-316 ovarian adenocarcinoma cell lines were exposed to 1.0 mM 1-octanol for 12 hr in order to evaluate the potential effects of inhibition of gap junction-mediated intercellular communication (GJIC) on cellular responses to the chemotherapeutic drug melphalan. Other cellular endpoints relevant to drug-resistance mechanisms which were monitored after treatments included cellular glutathione levels, glutathione S-transferase activity, mitochondrial membrane potential, and plasma membrane lipid mobility. In cells which were sensitive to melphalan, octanol enhanced melphalan toxicity in the GJIC-competent (A2780/S) but not GJIC-incompetent (COLO-316/S) sensitive cells. Although octanol increases plasma membrane lipid mobility in A2780/S and COLO-316/S, it appears that enhancement of A2780/S sensitivity to melphalan may be due to inhibition of GJIC. In melphalan-resistant cells (A2780/R and COLO-316/R), 1.0 mM octanol treatment for 12 hr combined with melphalan reversed the resistance of the cells to the drug. Therefore, alterations in cellular glutathione metabolism and effects on the plasma membrane in addition to uncoupling of GJIC may be involved in sensitizing communication-competent and communication-incompetent resistant cells because COLO-316/R lacks gap junction-mediated intercellular communication. Further, analysis of mitochondrial membrane potential provided an index of acquired drug resistance and the efficacy of melphalan and combined octanol/melphalan toxicity.

Topics: 1-Octanol; Adenocarcinoma; Cell Communication; Drug Resistance; Female; Gap Junctions; Glutathione; Glutathione Transferase; Humans; Melphalan; Membrane Fluidity; Membrane Potentials; Mitochondria; Octanols; Ovarian Neoplasms; Tumor Cells, Cultured

Colorectal adenocarcinomas are inherently resistant to anthracyclines and other topoisomerase-II inhibitors. Resistance to doxorubicin of colon cancer cells (Caco2) depends on 2 main mechanisms. The first is typical multi-drug resistance, characterized by the mdr1 gene and its product the P170 membrane glycoprotein. P170 effluxes anthracyclines out of cancer cells and is antagonized in vitro by verapamil. The second mechanism, which develops when cell-culture density increases, we have designated confluence-dependent resistance. Confluence-dependent resistance depends on the reduced topoisomerase II content of the G0/G1-phase cells which accumulate in the confluent population. We show here that short treatments of confluent Caco2 cells with slightly toxic concentrations of DNA-damaging agents (cisplatin, melphalan or mitomycin C) produced a transient accumulation of cells in S- and G2/M-phases of the cell cycle. Concomitantly with the increase in the S-phase population, the topoisomerase II cellular level and the sensitivity of cells to doxorubicin were greatly enhanced. Overcoming confluence-dependent resistance through S-phase accumulation and inhibition of multi-drug resistance by verapamil were fully additive, and a nearly complete reversal of confluent Caco2 cells' resistance to doxorubicin was obtained when both strategies were combined.

Topics: Adenocarcinoma; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Cycle; Cisplatin; Colonic Neoplasms; DNA Topoisomerases, Type II; Doxorubicin; Drug Resistance, Multiple; Drug Screening Assays, Antitumor; Humans; Melphalan; Mitomycins; Topoisomerase II Inhibitors; Tumor Cells, Cultured

Cyclocreatine, an analog of creatine, is an efficient substrate for creatine kinase, but its phosphorylated form is a poor phosphate donor in comparison with creatine phosphate. Cyclocreatine was not very cytotoxic upon 24 h of exposure of human SW2 small-cell lung cancer cells to concentrations of up to 5 mM. However, combinations of cyclocreatine (0.5 mM, 24 h) with each of four antitumor alkylating agents, cis-diamminedichloroplatinum(II), melphalan, 4-hydroperoxycyclophosphamide, and carmustine, resulted in additive to greater-than-additive cytotoxicity toward exponentially growing SW2 cells. The greatest levels of synergy were seen at higher concentrations of 4-hydroperoxycyclophosphamide and carmustine as determined by isobologram analysis. In vivo cyclocreatine (0.5 or 1 g/kg) was more effective if given i.v. rather than i.p. The longest tumor-growth delays, up to 10 days, were produced by extended regimens of cyclocreatine. Cyclocreatine was an effective addition to therapy with standard anticancer agents including cis-diamminedichloroplatinum(II), cyclophosphamide, Adriamycin, or 5-fluorouracil. No additional toxicity was observed when 10 days of cyclocreatine treatment was given with full standard-dose regimens of each drug. The resultant increases in tumor-growth delay were 1.7- to 2.4-fold as compared with those obtained for each of the drugs alone. These results indicate that cyclocreatine may be an effective single agent and an effective addition to combination chemotherapy regimens.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma, Small Cell; Carmustine; Cell Division; Cell Survival; Cisplatin; Creatinine; Cyclophosphamide; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Lung Neoplasms; Mammary Neoplasms, Experimental; Melphalan; Rats; Rats, Inbred F344; Tumor Cells, Cultured

Clinical trials combining paclitaxel with other active chemotherapy agents are currently underway. In vitro preclinical studies may assist in the selection of appropriate drug combinations or sequences for clinical investigation. We have used clonogenic cell survival assays and DNA flow cytometry to examine the effect of paclitaxel combined with melphalan, thiotepa, or cisplatin on the survival and cell-cycle parameters of human lung A549 and breast MCF-7 adenocarcinoma cells. A549 and MCF-7 cells were incubated with paclitaxel for 24 h, followed by a 1 h exposure to cisplatin, melphalan, or thiotepa. Both cell types were also incubated with cisplatin or an alkylator for 1 h followed by a 24 h paclitaxel exposure. When the paclitaxel exposure preceded either melphalan, thiotepa, or cisplatin, the cytotoxicity was additive for both cell lines tested. When cisplatin or alkylator exposure was given prior to the paclitaxel, cytotoxicity was also additive in MCF-7 cells. However, cisplatin or alkylators were antagonistic to paclitaxel cytotoxicity when they preceded the paclitaxel exposure in A549 cells (e.g., 2% survival with 100 nM paclitaxel vs. 7% survival with cisplatin and paclitaxel). Cell-cycle analysis revealed that exposure to 100 nM paclitaxel for 24 h blocked a majority of the cells into the G2/M phase (> or = 80% for A549 cells, 60-65% for MCF-7 cells). However, exposure to alkylators before incubation in paclitaxel reduced the proportion of A549 but not MCF-7 cells in G2/M--e.g., exposure to 30 micrograms/ml cisplatin prior to paclitaxel exposure caused only 25% of A549 and 55% of MCF-7 cells to block in G2/M.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Cell Death; Cisplatin; DNA, Neoplasm; Drug Administration Schedule; Flow Cytometry; Humans; Lung Neoplasms; Melphalan; Paclitaxel; Thiotepa; Tumor Cells, Cultured

We investigated the effect of DNA-repair-enzyme inhibitors on L-phenylalanine mustard (L-PAM) and cis-diamminedichloroplatinum (II) (CDDP) cytotoxicity in rat mammary-carcinoma MatB cells sensitive (WT) and resistant (MLNr) to bifunctional alkylating drugs. Among the modulators tested, the combination of arabinofuranosylcytosine (Ara-C) and hydroxyurea (HU) significantly increased the sensitivity of the cells to CDDP and, to a lesser extent, L-PAM as compared with cells treated with drug alone. The modulation effect of HU+Ara-C on CDDP and L-PAM cytotoxicity was more effective when intracellular glutathione (GSH) was depleted by L-buthionine-(S,R)-sulfoximine (BSO). This was also associated with a significant increase in DNA-DNA interstrand cross-links. Caffeine also sensitized both WT and MLNr cells to the cytotoxic effect of L-PAM and CDDP, and this effect was potentiated in GSH-depleted cells. No significant effect was observed with other repair modulators such as aphidicolin, 3-aminobenzamide, novobiocin, or etoposide. These results show (a) that inhibition of DNA repair by HU+Ara-C or caffeine could be a target for modulation of bifunctional alkylating-drug resistance and (b) that GSH depletion renders resistant cells more susceptible to the repair-enzyme modulators, suggesting that intracellular GSH may be involved in the regulation of some of these enzymes. Our results also indicate that a combination of a number of modulators may offer an advantage over the use of a single modulator in tumor resistance that may be associated with multifactorial mechanisms.

Topics: Adenocarcinoma; Alkylating Agents; Animals; Cisplatin; Cross-Linking Reagents; DNA Repair; DNA, Neoplasm; Drug Resistance; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glutathione; Mammary Neoplasms, Experimental; Melphalan; Rats; Tumor Cells, Cultured

The syntheses and cytotoxic activities of substituted N-phenylacetamido derivatives of doxorubicin and melphalan are described. The derivatives were designed as prodrugs which could be activated in a site-specific manner by monoclonal antibody-penicillin-G amidase (mAb-PGA) conjugates. N-(Phenylacetamido)doxorubicin (2) and N-(phenylacetyl)melphalan (6) were found to be 10- and 20-fold less cytotoxic against H2981 lung adenocarcinoma cells than doxorubicin and melphalan, respectively. When incubated with PGA, the cytotoxicity of 2 and 6 increased and became equivalent to that of the corresponding drugs from which they were made. The poor solubility characteristics of 2 in aqueous solutions provided the basis for the development of the more soluble doxorubicin derivatives, N-(4-aminophenylacetyl)doxorubicin (3) and N-(4-phosphonooxy)phenylacetyl)-doxorubicin (4). In vitro cytotoxicity assays indicated that 3 and 4 were at least 1000-fold less toxic than doxorubicin against H2981 cells. PGA and the mAb conjugate L6-PGA were able to effect the activation of 3 and 6 on H2981 cells (L6-antigen positive). Hydrolysis of the phosphate group of 4 was required prior to activation with PGA or L6-PGA. This was achieved using alkaline phosphatase, or by exposing 4 to phosphatases present in cell culture medium. The activation of 3, 4, and 6 on H2981 cells by L6-PGA occurred in an immunologically specific manner, since activation could be blocked by saturating cell surface antigens with L6 prior to treatment with L6-PGA. These results demonstrate that 3, 4, and 6 are prodrugs that can be specifically activated to release clinically approved anticancer agents by a mAb-PGA conjugate.

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Doxorubicin; Humans; Lung Neoplasms; Melphalan; Penicillin Amidase; Phenylacetates; Prodrugs; Structure-Activity Relationship; Tumor Cells, Cultured

Conventionally in vitro cytotoxicity assays are performed as single-end-point determinations. To compensate for the diversity of growth rates among different cell lines in this report we describe a computerized kinetic chemosensitivity assay based on quantification of biomass by staining cells with crystal violet. As a prerequisite four human breast cancer cell lines (MDA-MB-231, MCF-7, T-47-D and ZR-75-1) were characterized with regard to oestrogen and progesterone receptor content, modal chromosome number and proliferation kinetics depending on the number of passages in culture. With prolonged time in culture for ZR-75-1 exposed to various concentrations of cisplatinum a dose-related increase in drug effect was observed. Owing to a correction of the T/C values for the initial cell mass (at the time when drug is added) a sharp distinction between cytostatic and cytocidal drug effects becomes obvious in plots of corrected T/C values versus time of incubation. The influence of the untreated control on the corrected T/C values and possible time courses of theoretical inhibition profiles (reflecting cytostatic, transient cytotoxic or cytocidal drug effects as well as development of resistance) and their relationship to the corresponding growth curves of drug-treated cells are discussed. Chemosensitivity assays with diethylstilbestrol dipropionate, tamoxifen, melphalan, cisplatinum, vinblastine, Adriamycin and 5-fluorouracil prove the theoretical considerations to be true for MDA-MB-231, MCF-7, T-47-D and ZR-75-1 human breast cancer cell lines in practice.

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cell Division; Cisplatin; Diethylstilbestrol; Drug Screening Assays, Antitumor; Female; Fluorouracil; Gentian Violet; Humans; Kinetics; Melphalan; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Receptors, Progesterone; Tumor Cells, Cultured; Vinblastine

We have studied alterations in glutathione (GSH) levels and glutathione-S-transferase (GST) activity in a series of in vitro derived multidrug resistant and cisplatin resistant sublines of the human lung cancer lines NCI-H69 (small cell), COR-L23 (large cell) and MOR (adenocarcinoma). We have also investigated the effects of ethacrynic acid, a putative inhibitor of GSTs, on levels of GSH and GST activity and on cellular sensitivity to melphalan and to cisplatin. Neither GSH content nor GST activity were significantly greater in the resistant sublines compared with their respective parental lines. The only effects of treating with ethacrynic acid at doses of 1 microgram ml-1 and 3 micrograms ml-1 for 2 h were a reduction in GSH content in the cisplatin resistant subline H69/CPR at the 3 micrograms ml-1 dose, and an increase to over 140% of control at 1 microgram ml-1 and 3 micrograms ml-1 in the MOR parental line (MOR/P) and at 1 microgram ml-1 in the multidrug resistant subline MOR/R. Exposure of parental line COR-L23/P to 3 micrograms ml-1 and 6 micrograms ml-1 of ethacrynic acid for 24 h, however, increased the GSH content to over 300% and 500% of control respectively. Variable effects of ethacrynic acid on GST activity were seen in these cell lines. Doses of 1 microgram ml-1 and 3 micrograms ml-1 reduced activity to 59% and 48% of control respectively in multidrug resistant subline H69/LX4. On the other hand, activity was increased in the cisplatin resistant subline H69/CPR (to 146% and 218% of control) and in MOR/P (to 117% and 137% of control) by 1 microgram ml-1 and 3 micrograms ml-1 respectively of ethacrynic acid. Addition of ethacrynic acid (3 micrograms ml-1) to treatment of the cell lines with melphalan or with cisplatin did not alter the dose-response curves to these agents.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cisplatin; Drug Interactions; Drug Resistance; Drug Screening Assays, Antitumor; Ethacrynic Acid; Glutathione; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Tumor Cells, Cultured

We have studied the influence of the peripheral vasodilator hydralazine (HDZ) on the vasculature and blood perfusion of two members of a series of subcutaneous murine adenocarcinomata of the colon (MAC tumours), and the influence of HDZ on the efficacy and/or toxicity of TCNU and melphalan. The fluorescent DNA stain Hoechst 33342, showed that HDZ caused a shutdown of tumour vasculature, related in magnitude to both dose and tumour differentiation state; 10 mg kg-1 caused an 80% vascular shutdown of well differentiated MAC 26 tumours, but only a 50% shutdown of the poorly differentiated MAC 15A tumours. 2.5 mg kg-1 was ineffective. The blood perfusion marker 99mTc-HMPAO showed that the normal perfusion of MAC tumours was consistently markedly less than that of lung, liver or kidneys (4-5% of lung perfusion). HDZ (10 mg kg-1) decreased MAC 26 perfusion by 63%, and that of MAC 15A by 20%. Again, 2.5 mg kg-1) was ineffective. Use of in vivo to in vitro clonogenic assays showed that HDZ (10 mg kg-1) potentiated the efficacy of melphalan (1-10 mg kg-1 i.p.) by a factor of 2.1, and increased the efficacy of TCNU (1-10 mg kg-1 i.v., factor = 1.7) when given 10 or 15 min respectively after dosing. However, the addition of HDZ increased the acute bone marrow toxicity of melphalan, but not that of TCNU. The clinical relevance of these results is discussed.

Topics: Adenocarcinoma; Animals; Bone Marrow; Cell Division; Cell Line; Colonic Neoplasms; Hydralazine; Male; Melphalan; Mice; Mice, Inbred Strains; Nitrosourea Compounds; Radionuclide Imaging; Regional Blood Flow; Taurine; Tumor Stem Cell Assay

Pharmacokinetically guided administration of melphalan was investigated during a pilot study in patients with advanced ovarian adenocarcinoma. The schedule involved a fixed dose on day 1 (7.9 mg) followed by a second dose on day 2, calculated on the basis of pharmacokinetic data to achieve a target area under the concentration-time curve (AUC). 20 courses of intravenous melphalan were administered to 7 patients. AUC, standardised to 1 mg/m2, ranged between 4.3 and 8.9 (mg/l) min. In 12 fully evaluable courses, less than 15% deviation from the target AUC was found, showing that AUC monitoring was possible by means of the test dose. Pharmacodynamic effects showed a positive correlation with melphalan AUC. Myelosuppression appeared at 47 (mg/l) min and grade 3 or 4 haematological toxicities were observed in 4 cycles, associated with AUC values ranging between 86 and 112 (mg/l) min. Relative leucocyte decreases were well correlated with AUC values.

Topics: Adenocarcinoma; Aged; Bone Marrow; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Intravenous; Melphalan; Middle Aged; Ovarian Neoplasms; Pilot Projects

The ATP bioluminescence assay has demonstrated a strong potential to become a clinical assay for chemosensitivity testing. Currently, chemotherapy of gynecologic cancers remains controversial and empirical. To optimize the patient's chance of survival and to justify related toxicities, the chemoregimen should be individualized and based on the patient's chemosensitivity profiles. This study was performed to identify a panel of active drugs against uterine cancer cell lines for possible use in future chemosensitivity testing. We used the ATP chemosensitivity assays to screen 12 common cytotoxic agents against six uterine cancer cell lines. Drug concentrations required for a 50% surviving fraction were defined as IC50s. When using an IC50 of 0.21 PPC (peak plasma concentration) as a cutoff value for sensitivity, the following 8 drugs were considered effective for uterine cancer cell lines: actinomycin D, Adriamycin, vinblastine, etoposide, 5-fluorouracil, methotrexate, cytosine arabinoside, and mitomycin-C. Meanwhile, 4 drugs, cisplatin, 4OH-Cytoxan, bleomycin, and Alkeran with mean IC50s of 2.1 +/- 0.7, 0.8 +/- 0.1, greater than 5.0, and 0.75 +/- 0.36 PPC, respectively, were considered inactive or partially active with higher IC50s than peak plasma concentrations. In conclusion, the above panel of promising drugs can be further tested in animal models or human cancer specimens for possible use in chemosensitivity testing of uterine cancer patients.

Topics: Adenocarcinoma; Adenosine Triphosphate; Alkaloids; Antineoplastic Agents; Cisplatin; Cyclophosphamide; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Humans; Intercalating Agents; Kinetics; Luminescent Measurements; Melphalan; Mitomycin; Tumor Cells, Cultured; Uterine Neoplasms

We have derived sublines of three human lung cancer cell lines with acquired resistance to cisplatin. The cisplatin resistant sublines of NCI-H69 (small cell), COR-L23 (large cell), and MOR (adenocarcinoma) show 5.3 fold, 3.1 fold, and 3.8 fold resistance, respectively, determined in a 6-day MTT assay. Although the parent lines show a wide range of glutathione content per cell, the sublines each show similar values to their corresponding parent line. Radiation response curves have been obtained using a soft agar clonogenic assay. Values obtained for the parent lines (95% CL in parentheses) were: NCI-H69: Do = 0.99 Gy (0.87-1.16), n = 2.9 (1.6-5.2), GSH = 14 ng/10(4) cells; COR-L23: Do = 1.23 Gy (1.05-1.49), n = 1.3 (0.7-2.2), GSH = 47 ng/10(4) cells; MOR: Do = 1.66 Gy (1.48-1.88), n = 3.0 (1.9-4.8), GSH = 86 ng/10(4) cells. The cisplatin resistant variants of NCI-H69 and COR-L23 showed 31% and 63% increases, respectively, in Do compared to their parent lines, whereas no change in radiation response was seen in MOR. In this panel of lines, therefore, although there is a correlation between glutathione content and radiosensitivity of the parent cell lines, acquired resistance to cisplatin is not accompanied by increased glutathione content. However, two of the three cisplatin resistant lines do show a significantly reduced radiosensitivity.

Topics: Adenocarcinoma; Carcinoma; Carcinoma, Small Cell; Cisplatin; Dose-Response Relationship, Radiation; Drug Resistance; Glutathione; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Radiation Tolerance; Tumor Cells, Cultured

Failure of anti-cancer agents to reach all clonogenic cells at cytotoxic concentrations is recognized as an important form of resistance in solid tumours. Subcutaneously implanted mammary adenocarcinoma 16/C was used to evaluate the intratumour distribution of five alkylating, bioreductive alkylating and intercalating agents and two radiation sensitizers. The agents were classified according to their in vivo distribution in well- and poorly-perfused tumour regions, as delineated by lissamine green. The classifications were: (1) distribution in direct proportion to the vascular supply; (2) uniform distribution to well- and poorly-perfused tumour regions; and (3) preferential retention in the poorly-perfused tumour regions. Our current state of knowledge did not allow reliable prediction of the classification based on chemical structure or mechanism of action.

Topics: Adenocarcinoma; Alkylating Agents; Animals; Antineoplastic Agents; Antipyrine; Biological Transport; Breast Neoplasms; Carbon Radioisotopes; Cell Line; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Melphalan; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Transplantation, Heterologous

In the present investigations we evaluated the consequence of changing the cellular microenvironment on the treatment efficacy of the alkylating chemotherapeutic agent melphalan. Human A549 adenocarcinoma and mouse KHT/iv sarcoma cells were treated with melphalan under aerobic or hypoxic conditions at pH 6.6 or 7.4. Both low oxygenation and acidic pH individually were found to increase tumor cell killing by this chemotherapeutic agent. However, the magnitude of the enhanced toxic effect was greatest when hypoxic conditions and acidic pH were combined during treatment. For example, A549 cells treated with melphalan under hypoxic conditions at pH 6.6 were approximately 3 times more sensitive to this anticancer drug than were cells exposed in air at pH 7.4. Conditions of low oxygen and pH also increased the chemosensitization potential of the nitroimidazole misonidazole (MISO) when combined with this chemotherapeutic agent. Thus, when KHT/iv cells were treated with the combination of melphalan plus MISO, the resulting enhancement ratio increased from 1.8 to 2.5, when the pH maintained during the treatment was changed from physiologic (7.4) to acidic (6.6).

Topics: Adenocarcinoma; Animals; Cell Hypoxia; Humans; Hydrogen-Ion Concentration; Melphalan; Mice; Oxygen Consumption; Sarcoma, Experimental; Tumor Cells, Cultured; Tumor Stem Cell Assay

To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non-small cell lung cancer cell line (PC-9/CDDP) selected from the wild type (PC-9) for acquired resistance to cisplatin. PC-9/CDDP demonstrated 28-fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (X 6.3), melphalan (X 3.7) and 3-[(4-amino-2-methyl-5-pyrimidinyl)]methyl-1-(2-chloroethyl)-1-nitros our ea (ACNU) (x 3.9). There was no expression of mdr-1 mRNA in either wild-type or resistant cells. The mRNA and protein levels of glutathione S-transferase (GST) pi were similar in the two lines. A GST-mu isozyme was present in equal amounts and the activities of selenium-dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC-9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC-9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.

Topics: Adenocarcinoma; Blotting, Northern; Cell Survival; Chlorambucil; Cisplatin; Drug Resistance; Glutathione Transferase; Humans; Lung Neoplasms; Melphalan; Nimustine; RNA, Neoplasm; Tumor Cells, Cultured; Tumor Stem Cell Assay

Topics: Adenocarcinoma; Animals; Doxorubicin; Female; Follow-Up Studies; Mammary Neoplasms, Experimental; Melphalan; Mice; Perfusion

The pharmacokinetics and systemic availability of melphalan after high-dose oral administration with and without 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) or etoposide were examined in three patients undergoing autologous bone marrow transplantation. Patient 1 (advanced melanoma) received melphalan at 80 mg/m2/day p.o. on days -6, -5, and -4, followed by BCNU at 300 mg/m2/day i.v. on days -3, -2, and -1 prior to bone marrow transplantation. Patient 2 (advanced colon carcinoma) received melphalan at 75 mg/m2/day p.o. on days -3, -2, and -1. Patient 3 (advanced refractory lymphoma) received etoposide at 800 mg/m2/day i.v. on days -7, -5, and -3, followed by melphalan at 157 mg/m2/day p.o. on days -2 and -1. Melphalan was administered as a bolus oral dose, using 2-mg tablets. Blood samples were collected at 0, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 6, 8, 12, and 24 h after each dose of melphalan. Peak plasma melphalan concentrations in the three patients ranged from 0.354 (patient 2) to 1.768 micrograms/ml (patient 1). Plasma melphalan concentration X time products (C x Ts) showed extreme variability in one patient (patient 2), ranging from 0.76 to 4.48 micrograms.h/ml. To determine the relative systemic availability of orally administered melphalan, i.v. C X Ts proportional to the p.o. doses were extrapolated from previously reported i.v. bolus pharmacokinetic data. The p.o.:i.v. plasma C X T ratios for high-dose melphalan ranged between 0.09 (patient 3) and 0.58 (patient 2). Although these C X T data suggest a dose-response for orally administered melphalan, the systemic availability of these high p.o. melphalan doses was extremely variable, both within and between study patients. Thus, we cannot recommend the use of high-dose p.o. melphalan regimens in patients undergoing autologous bone marrow transplantation.

Topics: Adenocarcinoma; Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Bone Marrow Transplantation; Carmustine; Etoposide; Female; Humans; Injections, Intravenous; Lymphoma; Male; Melanoma; Melphalan; Middle Aged; Time Factors

236 patients with various advanced malignant solid tumors treated by combined chemotherapy with routine doses of cisplatin (DDP) from 1980 to 1986 are presented. According to different doses of cisplatin everyday, the patients were divided into 4 groups: 1. 20 mg/day x4-5, 80 cases; 2. 30 mg/day x3-5, 91 cases; 3. 40 mg/day x3-4, 37 cases; 4. 50 mg/day x2-3, 28 cases. Each group was repeated for 3 weeks. The effect and toxicity were analysed and compared with 22 cases treated by single DDP in 1975. The response (CR + PR) rate was 39.2% in 194 evaluated patients. The response rate was similar in group 20 mg and single DDP (29.2% and 27.3%). The response rate was lower than that of group 30 mg, 40 mg, and 50 mg (43.4%, 42.4%, and 50%) (P less than 0.05). The remissions in various groups were not significantly different. The toxicity of combined chemotherapy was not severe. 91.1% of patients had nausea and vomiting. There was no statistical difference in the various groups. Bone marrow suppression was less in single DDP group than that of combined chemotherapy group, (P less than 0.05). DDP 30 mg-50 mg 1/d x5-3 was better than HD-DDP in some patients.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Humans; Lomustine; Lung Neoplasms; Male; Melanoma; Melphalan; Methotrexate; Middle Aged; Neoplasms; Procarbazine; Testicular Neoplasms; Vincristine

To augment the antitumor effect of high-dose melphalan and determine pharmacokinetics we conducted a phase I trial of escalating doses of high-dose IV melphalan with the chemosensitizer misonidazole for patients with advanced colorectal carcinoma. Fourteen patients with modified Dukes D adenocarcinoma of the colorectum were treated with a single course of melphalan (40-60 mg/m2 i.v. bolus q.d. X 3 days) and misonidazole (1-3 g/m2 p.o. q.d. X 3 days) followed by autologous bone marrow transplantation. Toxicity consisted of severe myelosuppression, moderate nausea and vomiting, and mild mucositis and diarrhea. One patient developed unexplained renal tubular acidosis, and a diffuse encephalopathy occurred in another patient. Three patients died within the first 30 days after the start of treatment, two due to tumor progression and one due to sepsis and disseminated intravascular coagulation-induced intracerebral hemorrhage. Six of 14 patients achieved a partial response, and the median response duration was 4 months (range 3-10 months). Analysis of misonidazole serum concentrations showed similar pharmacokinetics to those previously reported, suggesting no significant drug interaction with intravenous melphalan. Mean peak serum concentrations ranged from 81.8 micrograms/ml to 115.2 micrograms/ml at the second and third misonidazole dose levels, which approximate those known to provide effective chemosensitization with melphalan in animal models. In this phase I study, we showed that maximally tolerated doses of intravenous melphalan can safely be combined with oral misonidazole. In view of the large volumes of oral misonidazole required at the highest dose level, subsequent studies to determine the maximally tolerated dose of misonidazole should employ the intravenous form.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melphalan; Middle Aged; Misonidazole; Neoplasm Metastasis; Rectal Neoplasms; Remission Induction

Patients with epithelial ovarian carcinoma (OVCA) and positive second-look operation (SLO) have a poor short-term prognosis. Treatment after SLO is still controversial and pilot studies are justified in an attempt to improve survival of these patients. As OVCA is known to be a chemosensitive tumor, it seems logical to treat these patients with high-dose chemotherapy with the support of an autologous bone marrow transplantation. Fourteen patients underwent primary surgery with tumor debulking followed by cis-platinum-based chemotherapy. SLO was performed in each patient and was microscopically positive in five and macroscopically positive with secondary debulking in nine. All patients were treated after SLO with high-dose melphalan (HDM), 140 mg/m2, and autologous bone marrow support. HDM was well tolerated, with a median time to granulocyte recovery of 21 days. There was no death due to treatment toxicity. The mean follow-up after SLO is 43 months. Five patients (35.7%) are disease free at 30 to 60 months after SLO with no further treatment and, thus, a good quality of life. Four patients are alive with recurrent disease. Five patients died of OVCA; actuarial 3-year survival is 64%. This therapeutic procedure is well tolerated and seems to provide long-term survival for patients with no complete response after first-line chemotherapy. Therefore, it might also be applied to patients at high risk of recurrence after a negative SLO.

Topics: Adenocarcinoma; Adult; Bone Marrow Transplantation; Carcinoma; Combined Modality Therapy; Female; Follow-Up Studies; Hematopoiesis; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Pilot Projects; Reoperation

A complete hematologic remission was achieved in a patient with therapy-related preleukemia and transfusion-dependent pancytopenia after treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). The patient remained in remission for nearly 1 year despite the discontinuation of GM-CSF treatment. Several lines of evidence suggest that normal hematopoiesis was restored after GM-CSF treatment. First, the cytogenetic anomaly, which was present before GM-CSF, completely disappeared after three cycles of treatment. Cytogenetic conversion was documented by conventional karyotypic evaluation of mitotic bone marrow cell preparations as well as by premature chromosome condensation analysis of the nonmitotic cells of bone marrow and peripheral blood. Second, the growth pattern and cycle status of bone marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells were found to be normal during remission. Third, X chromosome-linked restriction fragment length polymorphism-methylation analysis of DNA from mononuclear cells (greater than 80% lymphocytes) and mature myeloid elements showed a polyclonal pattern. These findings suggest that restoration of hematopoiesis in this patient after GM-CSF treatment may have resulted from suppression of the abnormal clone and a selective growth advantage of normal elements.

Topics: Adenocarcinoma; Blotting, Southern; Bone Marrow; Colony-Stimulating Factors; DNA; Erythrocyte Count; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematocrit; Hematopoiesis; Humans; Karyotyping; Leukocyte Count; Melphalan; Middle Aged; Platelet Count; Preleukemia; Recombinant Proteins

Topics: Adenocarcinoma; Administration, Oral; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Drug Combinations; Drug Evaluation; Female; gamma-Globulins; Humans; Immunotoxins; Liver Neoplasms; Male; Melphalan; Middle Aged; Stomach Neoplasms

Interdisciplinary protocols for management of advanced adenocarcinoma of the ovary have resulted in prolonged patient survival. A subset of patients is emerging in whom central nervous system (CNS) relapse occurs even following negative second-look procedures (SLP). Seven of 342 eligible patients entered in a National Cancer Institute of Canada Trial for Ovarian Cancer, from February 1, 1980 to March 31, 1984, had CNS relapse. All patients received adriamycin and cisplatin. SLP was performed in 5 patients, 3 of whom were complete responders (CR). Two additional patients failed to complete their chemotherapy and had progressive pelvic disease. The median age of these 7 patients was 57 years, their overall survival time was 28 months, compared with an average age of 58 years and survival of 21.6 months, for the entire group. Two patients had prolonged survival after their CNS relapse; 1 patient lived 26 months, and the other, who underwent craniotomy for primary management of the metastasis survived 18 months. Confirmation of metastatic disease was obtained in 4 of the 7 patients. The results of this study suggest that management of CNS involvement in adenocarcinoma of the ovary should be determined by overall performance status even in the presence of generalized disease.

Topics: Adenocarcinoma; Aged; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Humans; Melphalan; Meningeal Neoplasms; Middle Aged; Ovarian Neoplasms

The role of tumor-to-tumor variability in response to chemotherapy was investigated in mice bearing mammary adenocarcinoma 16/C treated with melphalan. Lissamine green, a triphenylmethane dye, was given systemically to delineate areas of perfusion in the tumors. The regions of low perfusion ranged from less than 10% to greater than 90% of the mass of individual tumors. The variation in perfusion was as large between bilateral tumors in a mouse as between tumors in different hosts. The presence of viable cells capable of continued growth in the regions of low perfusion was demonstrated by bioassay. Concentrations of melphalan following i.p. administration varied by as much as tenfold or more between regions of low and high perfusion. Concentrations of melphalan in the well-perfused regions were similar to plasma concentrations at 30 min after administration, but elimination from the plasma was more rapid. The levels of melphalan in the tumor were higher following the initial dose than following succeeding doses in a multiple dose schedule. The results indicate that tumor-to-tumor variations in perfusion and drug distribution are major factors in variable tumor response.

Topics: Adenocarcinoma; Animals; Cell Survival; Lissamine Green Dyes; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred C3H; Perfusion

The records of 23 patients with confirmed carcinoma of the fallopian tube, treated between 1966 and 1983, were reviewed. Patients ranged in age from 41 to 88 years. A pelvic mass was the most common preoperative finding (61%), followed by abnormal bleeding (43%), and pain (39%). Fifteen patients had stage I or II disease, 8 had Stage III or IV disease. In patients with metastatic disease, involvement of the peritoneal surfaces, bowel, and omentum were noted most often. Lymph nodes were the most common site(s) of recurrent disease. Twelve evaluable patients with measurable disease were treated with cisplatin and cyclophosphamide (PC) +/- doxorubicin (PAC). There were 9 complete and 2 partial responses, a 92% response rate. Incorporation of cisplatin therapy appears to have resulted in improved short-term survival.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Fallopian Tube Neoplasms; Female; Humans; Melphalan; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies

Using the triphenylmethane dye, lissamine green, as an indicator of blood perfusion, we have demonstrated that L-phenylalanine mustard (L-PAM) is differentially distributed in mice bearing mammary adenocarcinoma 16/C tumors. Following i.p. administration, concentrations of L-PAM in various regions of the tumors vary by as much as 10-fold or more between regions of low and high perfusion. Since the nitroimidazoles, metronidazole and misonidazole, increase the cytotoxicity of certain antitumor agents, these compounds were investigated for their ability to increase the distribution of L-PAM into tumor regions of low perfusion. Administration of metronidazole (400 mg/kg) or misonidazole (800 mg/kg) 1 h prior to L-PAM and lissamine green resulted in elevated plasma levels of L-PAM and increased concentrations of L-PAM in tumor regions of high perfusion. A slight increase in the normally low levels of L-PAM in tumor regions of low perfusion was observed but the increase was not statistically significant. In contrast to the uneven distribution of L-PAM, metronidazole and misonidazole were evenly distributed throughout plasma and tumor regions of both high and low perfusion. Bioassay of tumors following in vivo exposure to metronidazole and L-PAM indicated decreased viability in fragments from tumor regions of high perfusion, but not from tumor regions of low perfusion. These studies demonstrate that the nitroimidazoles increased L-PAM levels in plasma and in tumor regions of both high and low perfusion but did not induce a uniform distribution of L-PAM throughout the tumors. The nitroimidazoles may enhance the effectiveness of L-PAM as an antitumor agent by increasing the concentration of drug that reaches a tumor.

Topics: Adenocarcinoma; Animals; Female; Lissamine Green Dyes; Mammary Neoplasms, Experimental; Melphalan; Metronidazole; Mice; Misonidazole; Nitroimidazoles; Time Factors

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Copper; Dipeptides; Drug Evaluation, Preclinical; Intestinal Neoplasms; Intestine, Large; Leukemia, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental; Organometallic Compounds

Thirty-one patients with histologically confirmed FIGO Stage II adenocarcinoma of the ovary were prospectively treated in two sequential studies: 3000 rad of whole abdominal radiation therapy over 6 weeks by an open field technique followed by 2000 rad pelvic boost over 2 weeks (group 1, 16 patients, 1972-1974) or 5000 rad of pelvic radiation therapy over 5 weeks followed by a year of melphalan chemotherapy at a dose of 0.2 mg/kg/day for 5 days every 4 weeks (group 2, 15 patients, 1975-1982). Abdominal radiation included the entire peritoneal cavity and both diaphragms; the liver was not shielded. Only 2 patients had residual disease greater than 2 cm. No group 1 patients underwent pretherapy restaging laparoscopy prior to radiation or second look laparotomy after treatment. Eighty percent of group 2 patients underwent restaging laparoscopy (10) or staging laparotomy (2) prior to radiation. All group 2 patients underwent second look procedures if no evidence of disease. No patient developed intestinal complications secondary to radiation requiring surgery. Eighty-one percent of group 1 patients and to date 40% of group 2 patients developed recurrences. Size of residual disease prior to radiation, histologic grade, and substage (IIA, B, or C) did not correlate with recurrences. Five-year estimated survival was 40 and 50% for groups 1 and 2, respectively. Three thousand rad of wole abdominal radiation plus 2000 rad pelvic boost or 5000 rad pelvic radiation plus melphalan did not appear to improve survival over surgery alone. The role of radiation therapy in Stage II ovarian cancer remains unclear.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Combined Modality Therapy; Enteritis; Female; Humans; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Radiation Injuries; Radiotherapy

From 1980 to 1984 fifty-four patients with advanced ovarian carcinoma after operation and concluding chemotherapy with alkeran (n = 7) or cis-platin/alkeran +/- hexamethylmelamine (n = 47) as well as second-look laparotomy received follow-up radiotherapy either with the moving-strip technique (n = 35) or later the open-field technique (n = 19). 32 patients in CR received radiation therapy. 15 patients in CR are without relapse after undergoing open-field radiation therapy and a mean observation period of 25 months. At this point of time 5 of 17 patients had relapses under the moving-strip radiation treatment. The frequency of the relapses is apparently due to the very long periods of radiation and numerous interruptions in treatment. If residual tumors were present at the begin of ray therapy, a CR could only be achieved in cases where the previous monotherapy was with alkeran.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Combined Modality Therapy; Endometriosis; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis; Reoperation

In human tumor cells freshly obtained from patients with breast cancer, ovarian cancer, or adenocarcinoma of unknown etiology and in normal human bone marrow cells, the cell-to-medium ratio (intracellular/extracellular concentration) in vitro of 5.42 microM melphalan rose rapidly to levels of 6-17 after 35 min at 37 degrees C in Dulbecco's phosphate-buffered saline containing bovine serum albumin and glucose. Only patient C (breast cancer) had received chemotherapy. In all cells studied, L amino acids (1 mM) such as leucine, glutamine, tyrosine, and methionine reduced the cell-to-medium ratio of melphalan at 3 and 35 min. There was a good correlation between the reduction of melphalan transport at 35 min in the heterogeneous nucleated bone marrow cell population by amino acids and their effect on melphalan cytotoxicity in the CFU-C system. Aminoisobutyric acid (A1B), a specific substrate of the A system of amino acid transport, at a concentration between 1 and 50 mM had no significant effect on melphalan uptake at 3 min in any of the human cells studied except those of patient C. At 35 min A1B (10 or 50 mM) significantly reduced the intracellular melphalan concentration in normal bone marrow cells and tumor cells from patients B and C. At 2 mM, 2-aminobicyclo-(2, 2,1)-heptane-2-carboxylic acid (BCH), a specific substrate of the L system of amino acid transport, reduced the cell-to-medium ratio to 70% of control at 3 and 35 min in human bone marrow cells. In tumor cells from patients A, B, D, and F, 2 mM BCH had no significant effect on melphalan uptake at 3 min; it slightly decreased uptake in tumor cells from patient C. At 35 min, 2 mM BCH significantly reduced melphalan transport in tumor cells from patients C and F only. The lack of a BCH-suppressible component to melphalan uptake into human tumor cells freshly obtained from previously untreated patients contrasts with the presence of this component in murine L1210 leukemia cells, murine P388 leukemia cells, and human tumor cell lines. This suggests that minor differences in melphalan transport may exist amongst species and also between human tumor cells which are freshly obtained and cell lines maintained in culture.

Topics: Adenocarcinoma; Amino Acids; Amino Acids, Cyclic; Animals; Biological Transport; Bone Marrow; Breast Neoplasms; Cell Line; Cell Survival; Chromatography, Thin Layer; Colony-Forming Units Assay; Culture Media; Female; Humans; Kinetics; Melphalan; Mice; Neoplasms

One hundred and thirty three specimens from mammary and ovarian adenocarcinoma and from melanoma were cultured according to an agar/agar clonogenic assay. Melanoma and ovarian cancers exhibited a 70 per cent rate of success for culture; 50 per cent of the mammary adenocarcinomas were successfully cultured. Fifty-nine ovarian cancers were cultured in order to test the in vitro effectiveness of Cisplatinum and Adriamycin. Thirty percent of cultured tumors gave rise to relevant chemograms. The chemoresistance measured in vitro was correlated to the ineffectiveness of the patient's treatment. In contrast, we were unable to predict chemosensitivity. Taking into account the technical difficulties encountered in these assays, human tumor clonogenic assays cannot at present be proposed as a routine procedure in the prediction of the effectiveness of chemotherapeutic treatments. Nevertheless, they must be developed in order to determine the spectrum of activity of new antineoplastic agents on various human tumors.

Topics: Adenocarcinoma; Agar; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cisplatin; Colony-Forming Units Assay; Cyclophosphamide; Doxorubicin; Drug Resistance; Female; Humans; Melanoma; Melphalan; Ovarian Neoplasms; Tumor Stem Cell Assay

Sixty-eight patients with "advanced ovarian carcinoma" were entered into an ongoing phase-II trial for remission induction with cis-platinum (DDP) 80 mg/m2 i.v. on day 1 followed by forced saline diuresis, melphalan (L-PAM) 12 mg/m2 i.v. on day 2 and hexamethylmelamine (HMM) 130 mg/m2 p.o. X 14 days from days 8-21 in six monthly cycles following operative resection and/or staging. Fifty-one patients were evaluable for response, ten had not completed six courses and could not be assessed, two patients died early (one probably of toxicity), and five patients refused treatment and follow-up. Thirty-Two patients had serous, endometrioid or undifferentiated carcinomas of the ovary. Of these, 11 (35%) achieved a pathologically proven complete remission (CR), five (16%) were NED after second-look (residual disease in ovary or removed omentum with all other biopsies and cytology washings negative), eight (32%) achieved a partial remission (PR), and three (12%) had progressive disease. None of the seven patients with clear-cell carcinoma and none of the three patients with Mullerian tumor of the ovary responded. Six of nine patients with tumors of uncertain origin or proven metastasis to ovary did not respond to treatment. These preliminary results indicate that advanced ovarian carcinomas form a heterogeneous group of recognizable neoplastic diseases with striking variation in response to treatment.

Topics: Adenocarcinoma; Altretamine; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Evaluation; Female; Humans; Melphalan; Middle Aged; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Prognosis; Reoperation

Autologous bone marrow rescue circumvents the major toxicity of most cancer chemotherapeutic agents. Melphalan is a particularly well suited agent for use with autologous bone marrow rescue and produces response in chemo-resistant tumours. Thirteen patients have been treated with high dose melphalan with autologous bone marrow rescue in this department. The aims of treatment were palliation, debulking of non-resectable tumours and curative adjuvant therapy. Three patients died of melphalan related toxicity. Of the remaining ten patients there were five partial remissions, one objective response, one complete remission, one with no response and two patients in whom the response is not yet assessable (adjuvant therapy). In our experience high dose melphalan is an effective means of killing tumour cells which are not sensitive to chemotherapy at conventional doses. It is recommended in young patients who have not had extensive previous radio- or chemotherapy, in the early stages of disease, with cure or prolonged remission the aim. High dose melphalan is not recommended in the older patient or in those with massive diseases and is no longer used with palliative intent.

Topics: Adenocarcinoma; Adolescent; Adult; Bone Marrow Transplantation; Female; Humans; Lung Neoplasms; Male; Melphalan; Middle Aged; Neoplasms; Osteosarcoma; Pelvic Neoplasms; Teratoma

The sensitivity of 12 human tumors to various chemotherapeutic agents was measured in the 6-day subrenal capsule xenograft assay. All of the tumors were adenocarcinomas: 9 ovarian, 2 colon, and one endometrial. Doxorubicin, cisplatin, melphalan, 5- fluorouracil , methotrexate, and vinblastine sulfate were tested for antineoplastic activity on all tumors. In addition, a prostaglandin synthetase inhibitor, sodium ibuprofen, was assayed for cytostatic activity and for the ability to enhance the cytotoxic activity of melphalan and vinblastine sulfate. The response of the tumors to the cytotoxic agents were variable, but 5 of the 12 tumors showed a significant reduction of growth when the animals were treated with sodium ibuprofen alone. The addition of ibuprofen to the chemotherapeutic agents did not significantly alter the therapeutic activity of melphalan, but decreased the effectiveness of vinblastine in one case. When ibuprofen was given in combination with a cytotoxic drug, the primary cytoreductive effect was that of the cytotoxic agent.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclooxygenase Inhibitors; Humans; Ibuprofen; Melphalan; Mice; Neoplasm Transplantation; Tumor Stem Cell Assay; Vinblastine

A patient who presented simultaneously with typical hairy cell leukaemia (HCL) and multiple myeloma (MM) is described. He was treated with melphalan and irradiation and 18 months later presented with an adenocarcinoma. The occurrence of multiple neoplasms in this patient may reflect an underlying predisposition to neoplasia secondary to the immunological defects common in B cell lymphoproliferative diseases.

Topics: Adenocarcinoma; Aged; Blood Transfusion; Humans; Immunoglobulin A; Immunoglobulin kappa-Chains; Intestine, Small; Leukemia, Hairy Cell; Male; Melphalan; Multiple Myeloma; Plasma Cells; Splenectomy

Seventy-one cases of primary adenocarcinoma of the fallopian tube treated at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston were reviewed. The most common presenting symptoms were abdominal pain, abnormal uterine bleeding, and vaginal discharge. The most common physical finding was a palpable abdominal or pelvic mass. The preoperative diagnosis was correct for two patients. Initial therapy consisted of surgery alone, surgery plus radiation therapy, surgery plus chemotherapy, and a combination of surgery, chemotherapy, and radiation therapy in 10, 32, 21, and eight cases, respectively. The median survival for patients in these treatment groups was 33, 22, 27, and 22 months, respectively; the median survival for all patients was 23 months. No statistically significant differences emerged among the survival curves of patients treated with each of the above regimens.

Topics: Adenocarcinoma; Adenocarcinoma, Papillary; Adult; Aged; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Combined Modality Therapy; Fallopian Tube Neoplasms; Female; Humans; Melphalan; Middle Aged; Progestins; Time Factors

Melphalan (L-PAM) was compared to (C) cyclophosphamide, (M) methotrexate, and (F) 5-fluorouracil (CMF) in 413 patients with advanced ovarian carcinoma. L-PAM was given 3.5 mg/m2 twice daily for 5 days every 5 weeks. CMF doses were: C, 400 mg/m2; M, 15 mg/m2; and F, 400 mg/m2 IV on days 1 and 8 every 28 days. Three hundred seventy-five patients have been analyzed (L-PAM, 190; CMF, 185). One hundred fifty-three patients (41%) had measurable disease, 109 (29%) had evaluable disease, and 113 (30%) had nonmeasurable, nonevaluable disease. Response rates for patients with measurable and evaluable disease combined were similar: L-PAM, 32/130 (24%) (15% complete response); CMF, 47/132 (35%) (18% complete response). Patients with Stage IV measurable disease had a greater response rate to CMF, 22/52 (42%) versus L-PAM, 6/39 (15%). Survival and time to treatment failure were similar for both treatment regimens. Survival was improved in responders. Medians are: complete response, 28.1 months; partial response, 12.3 months; and no response, 6.7 months. Disease stage, performance status and age were identified as important prognostic variables for both survival and time to treatment failure.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Probability; Random Allocation; Time Factors

The paper presents the results of intratumoral chemotherapy of 32 cases of single metastases of stage III-IV ovarian cancer into the Douglas pouch. The metastases were detected at different stages after primary treatment. Thiotepa, cyclophosphamide, sarcolysin and methotrexate were administered in 81.2, 9.4, 6.2 and 3.1% of cases, respectively. A clinically-significant effect was recorded in 14 out of 32 cases (43.7%); tumor process was arrested in 15 cases (46.9%); treatment failed in 3 cases (9.4%). Toxic side-effects were less frequent and pronounced than in patients given standard systemic monochemotherapy.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Agents; Cyclophosphamide; Cystadenocarcinoma; Douglas' Pouch; Endometriosis; Female; Humans; Melphalan; Methotrexate; Middle Aged; Ovarian Neoplasms; Peritoneal Neoplasms; Thiotepa

Fourteen patients with advanced ovarian epithelial carcinoma were treated with a combination of chemotherapy and immunotherapy. The chemotherapy consisted of either melphalan or a combination of adriamycin, cytoxan, and cisplatin. The immunotherapy consisted of the injection of autologous radiation-attenuated tumor and Corynebacterium parvum. No significant toxicity occurred as a result of the immunotherapy, and there was no evidence of tumor growth at the sites of injection. The autologous tumor skin test showed prognostic value. Skin testing with C parvum was of less prognostic value than tumor. All other studies of immunologic status, including T- and B-cell enumeration and blastogenic responsiveness of the patients' lymphocytes to autologous tumor and mitogens, were of no prognostic value.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bacterial Vaccines; Cells, Cultured; Combined Modality Therapy; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Propionibacterium acnes; Skin Tests

Because of an encouraging response rate in a pilot study of adriamycin, BCNU, and cyclophosphamide (ABC), the Southeastern Cancer Study Group conducted a phase II study of ABC in patients with melphalan-resistant ovarian carcinoma. Of 36 evaluable patients, there were only 4 partial responses to therapy, for a partial response rate of 11%. Durations of response were 4 to 50 + weeks, and the overall median survival was 29 weeks. No complete responses were seen. Dose-limiting toxicity was granulocytopenia. We conclude that ABC is generally ineffective in management of alkylator-resistant ovarian adenocarcinoma.

Topics: Adenocarcinoma; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Drug Evaluation; Drug Resistance; Drug Therapy, Combination; Female; Humans; Melphalan; Ovarian Neoplasms

The data on 41 patients with epithelial malignant tumors of the ovaries, who received sarcolysin at different stages of combined treatment, were analyzed. The following factors of therapeutic effect of sarcolysin were established: age of 41-50 years, presence of ascites, administration by two routes--intravenously and intracavitarily and a total dose in excess of 160 mg. Still another factor is contributed by the extent of surgical procedure carried out as primary treatment.

Topics: Adenocarcinoma; Adult; Cystadenocarcinoma; Endometriosis; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms

Between 1958 and 1973, 2412 women with epithelial ovarian carcinoma were treated at Radiumhemmet. Of these tumors, 14.5 per cent were of borderline malignancy. The 5-year relative survival rate was 34 per cent among the patients with true malignant tumor and 93 per cent in the borderline cases. Even in advanced stages (IIb-IV) the 5-year survival rate was 78 per cent in the borderline cases. Advanced stage and high age at diagnosis, true malignancy and tumors of serous, clear cell or anaplastic type were associated with poor prognosis. The 5-year relative survival rate of patients with epithelial ovarian carcinoma in an early stage improved during the period, from 67 to 81 per cent.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoma; Endometriosis; Female; Follow-Up Studies; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Prognosis; Radiotherapy Dosage; Statistics as Topic; Time Factors

Topics: Adenocarcinoma; Animals; Carbon Radioisotopes; Female; Injections, Subcutaneous; Liposomes; Lymph Nodes; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Melphalan; Rats; Rats, Inbred F344

In mice with a transplantable mammary carcinoma, treatment with the prostaglandin-synthesis inhibitors flurbiprofen or indomethacin produced various beneficial effects. Survival time after excision of the transplanted tumour was increase, particularly when the drugs were given with the chemotherapeutic agents methrotrexate and melphalan, and there were more disease-free survivors. The combined treatment with flurbiprofen also gave less tumour recurrence at the excision site. Flurbiprofen did not seem to alter the bioavailability of the chemotherapeutic agents.

Topics: Adenocarcinoma; Animals; Biological Availability; Body Weight; Drug Therapy, Combination; Female; Flurbiprofen; Indomethacin; Male; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Neoplasm Recurrence, Local; Propionates; Prostaglandin Antagonists

After perioperative adjuvant chemotherapy of a sigma-adenocarcinoma with 400 mg peptichemio and 500 mg 5-fluorouracil a 61-year-old woman developed a severe intoxication: myelosuppression with pancytopenia, gastroenteritis and ulcerative proctitis, toxic hepato- and myocardiopathy, impaired renal function and alopecia. As a result of reduced resistance pneumonias, urinary tract infection, sepsis, cytomegaly infection and candidiasis of the oral mucosa occurred. The toxic effects are attributed mainly to the high dose of peptichemio.

Topics: Adenocarcinoma; Alopecia; Candidiasis, Oral; Diarrhea; Female; Fluorouracil; Hepatomegaly; Humans; Melphalan; Middle Aged; Peptichemio; Sigmoid Neoplasms

The present work uses an in vitro test model to measure the sensitivity of human ovarian cancer cells to Melphalan and Melphalan combined with Adriamycin. With this model we studied the possible correlation between the in vitro results and the response to these cytostatic drugs in vivo. Cancer cells from 20 patients with advanced ovarian cancer were tested. The in vitro effects of the drugs were measured as differences in incorporation of labeled 3H-thymidine in drug containing tubes and in control tubes. The effects of the drugs on the different cancer cells varied greatly from strong sensitivity to resistance. In vitro and in vivo results were compared one year after start of patient treatment. The overall agreement was 16/20, 80%. The in vitro method thus estimates a tumor cell characteristic which has a biological meaning also in in vivo conditions.

Topics: Adenocarcinoma; Carcinoma; Cells, Cultured; Doxorubicin; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endometriosis; Female; Humans; In Vitro Techniques; Melphalan; Ovarian Neoplasms; Retrospective Studies

Thirty-seven of 137 patients had a "second-look" laparotomy in the course of their management of carcinoma of the ovary. Patients were stratified according to three indications: (1) evaluation of disease with intent of stopping therapy, (2) assessment of signs of recurrent or persistent disease with a view to debulking tumor mass and changing chemotherapy, and (3) further tumor resection following cis-platinum combination therapy and determination of further chemotherapeutic agents. "Second-look" laparotomy may be performed after a shorter time interval when combination therapy is given because of the dose-limiting side effects of some of these agents and a more aggressive surgical approach in debulking tumors. At the time of laparotomy, cytologic testing is performed on the peritoneal fluid, and only areas suspicious for malignancy are biopsied. Thirteen percent of patients with no evidence of disease at "second-look" laparotomy developed recurrent disease. Twenty-nine percent of patients classified as clinically free of disease had malignancy present at the time of operation. Continued routine use of "second-look" laparotomy after appropriate chemotherapy is recommended.

Topics: Adenocarcinoma; Ascitic Fluid; Biopsy; Cisplatin; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Humans; Laparotomy; Melphalan; Neoplasm Staging; Ovarian Neoplasms; Recurrence; Time Factors

The effect of melphalan on the growth of 4 different lines of human lung-tumour xenografts has been established. The oat-cell carcinoma was the most sensitive, whereas the adenocarcinoma was the most resistant. Two lines of large-cell anaplastic carcinomas were intermediate in sensitivity. The differences in sensitivity were not reflected in the gross uptake of drug into the tumours. There was, with the exception of the adenocarcinoma line, a marked decrease in uptake per g tumour with increasing tumour size. This was partly caused by a decrease in the vascular supply in the same tumours with increasing tumour size. Extravasation of plasma proteins increased with increasing tumour size in all tumours, but was much less pronounced in the adenocarcinoma than in the other tumour lines. The extracellular volume of the various tumour lines did not vary with tumour size.

Topics: Adenocarcinoma; Animals; Capillary Permeability; Carcinoma, Small Cell; Cell Line; Erythrocyte Volume; Extracellular Space; Humans; Lung Neoplasms; Male; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms, Experimental; Plasma Volume; Transplantation, Heterologous

Primary carcinoma of the fallopian tube is a rare condition and not easy to diagnose. On a smear taken from the vagina of a 73-year-old woman, cells consistent with adenocarcinoma were detected even though the patient was asymptomatic. The specimen from endometrial curettage was normal on microscopic examination. The patient was readmitted, 2 months after dilatation and curettage, with a right pleural effusion. Examination of the pleural fluid revealed adenocarcinomatous cells. Laparotomy disclosed a primary carcinoma (stage IV) of the left fallopian tube. Thiotepa (45 mg) was instilled into the chest cavity and medroxyprogesterone (100 mg tid) and melphalan (6 mg/d for 4 days over 6 weeks) were given. Although the life expectancy for stage IV primary carcinoma of the fallopian tube is less than 2 years this patient has no clinical evidence of disease 2 1/2 years after operation.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Fallopian Tube Neoplasms; Female; Follow-Up Studies; Humans; Medroxyprogesterone; Melphalan; Middle Aged; Thiotepa

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Female; Humans; Leukemia, Erythroblastic, Acute; Melphalan; Pulmonary Fibrosis; Radiotherapy; Remission, Spontaneous

Topics: Adenocarcinoma; Female; Fluorouracil; Gastroenteritis; Humans; Leukopenia; Melphalan; Middle Aged; Peptichemio; Sigmoid Neoplasms

Two patients with measurable recurrent endometrial adenocarcinoma achieved complete remission proven by second-look operation. Both patients were treated with a combination of melphalan, 5-fluorouracil and medroxyprogesterone acetate.

Topics: Adenocarcinoma; Aged; Drug Therapy, Combination; Female; Fluorouracil; Humans; Medroxyprogesterone; Melphalan; Middle Aged; Uterine Neoplasms

In 1970, a prospective multidisciplinary protocol was initiated for Stages I through III obviously malignant ovarian epithelial carcinomas. The planned sequential therapy included 1) surgery, 2) radiotherapy (2000 rads to whole abdomen, 3000 rad boost to pelvis), 3) chemotherapy (ten cycles of Alkeran), and 4) a "second-look" surgical procedure. Ninety-six patients were enrolled in this program through 1976. Median follow-up of the survivors was greater than 44 months. Adjusted disease-free survival was 90 percent for Stage I, 64 percent for Stages IIB--IIC, and 16 percent for Stage III. Stage III patients with no palpable tumor at time of initiation of radiation therapy had a survival of 37 percent. No Stage III patient with palpable tumor at time of initiation of radiation therapy was cured. Eight percent of patients developed small bowel obstruction requiring surgical intervention. Three percent of all patients died of hematologic causes; of the 30-month-plus survivors, 5 percent (2 of 37) developed acute myelogenous leukemia. Cure and toxicity will be examined in detail and compared with the literature.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Female; Humans; Intestinal Obstruction; Melphalan; Mesonephroma; Neoplasm Recurrence, Local; Neoplasm Staging; Ovarian Neoplasms; Pilot Projects; Prospective Studies; Radiotherapy; Time Factors

Treatment of DBA/2J mice bearing a T1699 syngeneic mammary adenocarcinoma (Ts) with a single intraperitoneal (i.p.) injection of 100 ug melphalan produced complete tumor regression in about 65% of the animals treated; however, tumors recurred in about 85% of these regressors after 15-25 days' remission. The drug regimen was ineffective against Ts tumors growing in immunosuppressed or immunodeficient animals. Stimulation of immunologically intact Ts tumor-bearers with bacterial lipopolysaccharide (LPS) or with phytohemagglutinin (PHA) 3 days prior to melphalan therapy, on the other hand, produced not only higher rates of tumor regression but also significant increases in the number of permanent cures. A tumor induced by T1699 subline TR2 was resistant to the same regimen, although Ts and TR2 cells were equally susceptible to the cytotoxic and growth-inhibiting activities of the drug in vitro. In contrast, the combination of specifically armed monocytes and melphalan in vitro produced enhanced killing of Ts cells but not of TR2 cells. Analysis of the collaborative cytotoxicity between immune effector cells and melphalan indicated that exposure of tumor cells to killer cells increased the drug susceptibility of the tumor cells, but not the reverse. These results suggest a possible mechanism for in vivo resistance of tumors to chemotherapeutic agents that is not directly associated with the drug resistance of the tumor cells in vitro.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Cytotoxicity Tests, Immunologic; Drug Resistance; Female; Lipopolysaccharides; Mammary Neoplasms, Experimental; Melphalan; Mice; Monocytes; Phytohemagglutinins; T-Lymphocytes

Topics: Adenocarcinoma; Bundle-Branch Block; Doxorubicin; Female; Humans; Melphalan; Middle Aged; Postoperative Care; Uterine Neoplasms

Topics: Adenocarcinoma; Animals; Drug Evaluation, Preclinical; Female; Flurbiprofen; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Neoplasm Recurrence, Local; Propionates; Prostaglandin Antagonists

An unambiguous and sensitive method based on gas chromatography-chemical ionization-mass spectrometry has been developed to quantitate L-phenylalanine mustard and has been applied to measure levels in plasma of five patients receiving 0.15 to 0.25 mg/kg (10 to 17 mg) of the drug p.o. Peak plasma levels of 50 to 190 ng/ml were found to occur between 0.7 and 2.3 hr after ingestion. The time for the plasma level to fall to one-half of the peak value varied from 0.6 to 3 hr, and very low levels (less than 2 ng/ml) were present by 24 hr.

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Female; Gas Chromatography-Mass Spectrometry; Humans; Melphalan; Mesothelioma; Multiple Myeloma; Ovarian Neoplasms; Time Factors

The purpose of this study was to evaluate therapy with melphalan, 5-fluorouracil (5-FU), and medroxyprogesterone acetate combination (MFP) in women with metastatic or recurrent endometrial carcinoma not amenable to surgery or radiation therapy, as compared to progesterone therapy alone. Previously, the authors have treated 114 women with progesterone therapy and achieved a 15.8% objective response rate; 7.0% were complete responders. Thirteen women with documented recurrent or metastatic endometrial carcinoma were entered into the MFP study. Thirteen were evaluable for toxicity and 11 for response (2 had no measureable parameter). Treatment consisted of melphalan 0.2 mg/kg/day for 4 days every 4 weeks; 5-FU 15 mg/kg/day for 4 days every 4 weeks; and medroxyprogesterone acetate 1.0 g intramuscularly weekly. Two of the first 3 patients who were treated with this regimen developed severe thrombocytopenia (platelets, 25,000 and 17,000/mm3). Therefore, the remaining 10 patients received 5-FU at a dose of 10 mg/kg/day for 4 days every 4 weeks. Except for 1 patient who devloped thrombophlebitis, there was no other significant toxicity in the 90 courses of therapy received by the 13 women. Of the 11 women evaluable for respone, 6 (54.5%) responded (2 complete responders, 4 partial responders), 2 for stationary disease, and 3 progressed after having had stationary disease for 3, 6, and 9 months, respectively. Of special interest was that the 2 women with adenosquamous carcinoma responded and 1 additional patient with adenocarcinoma maintained a complete response with 5-FU therapy alone.

Topics: Adenocarcinoma; Antineoplastic Agents; Drug Therapy, Combination; Female; Fluorouracil; Humans; Medroxyprogesterone; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Uterine Neoplasms

Two studies were performed on female Fischer rats, housed 2/cage with food and water ad libitum in rooms maintained at 24 degrees C and with lights on daily for 8 hours (LD 8:16). In each study 192 rats were innoculated subcutaneously with 13762 mammary adenocarcinoma. Of these, 168 received chemotherapy, separate groups being treated at 1 of 6 different circadian stages. As controls, 24 tumour-bearing rats received saline while 24 rats without tumours received therapy. Chemotherapy consisted of 0.8 mg/kg Adriamycin (ADR) i.p. daily from day 11 to day 19 post tumour inoculation (except for days 16 and 17) followed by 1.6 mg/kg phenylalanine mustard (PAM) p.o. 3 times weekly beginning on day 20. In study-I PAM treatment was continued until 50% of the treated tumour-bearing rats died. In Study-II a 50% overall reduction in mean tumour size was not achieved before regrowth, presumably due to differences in the source of the rats, tumour-heterogeneity and/or other factors. At 50% overall tumour size reduction in the first study there was a statistically significant effect of treatment-timing on tumour size and on percent remission. The greatest reduction in mean tumour size and the highest percentage remission was observed in rats treated at the onset of darkness (activity), a timing similar to that observed in previous studies for optimal tolerance of ADR and PAM by the host. No deaths were observed in treated rats without tumours. When the drug combination used was sufficiently active against the tumour, the therapeutic index (selective toxicity) was improved by timing therapy according to circadian rhythms in the tumour-host system. This effect was achieved with doses not lethal to the nontumourous host. The presumption by others that chronotherapy depends on the use of toxic doses does not here apply.

Topics: Adenocarcinoma; Animals; Cell Line; Circadian Rhythm; Doxorubicin; Drug Therapy, Combination; Female; Mammary Neoplasms, Experimental; Melphalan; Rats; Rats, Inbred F344

Topics: Adenocarcinoma; Animals; Antibodies, Neoplasm; B-Lymphocytes; Dose-Response Relationship, Immunologic; Female; Macrophages; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasm Regression, Spontaneous; T-Lymphocytes

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Humans; Male; Melphalan; Middle Aged; Prostatic Neoplasms; Remission, Spontaneous; Time Factors

Topics: Adenocarcinoma; Amino Acids; Animals; Antineoplastic Agents; Copper; Drug Therapy, Combination; Female; Intestinal Neoplasms; Lung Neoplasms; Mammary Neoplasms, Experimental; Melphalan; Mice; Neoplasms, Experimental; Rumen; Sarcoma 37; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Animals; Cell Division; Chromosome Aberrations; Female; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation; Rats; Rats, Inbred F344; Species Specificity; Transplantation, Heterologous; Transplantation, Isogeneic

Therapeutic properties of cis-dichlorodiammineplatinum (II) were studied on 12 strains of transplantable tumors and leukemias in mice. The compound is characterized by a wide spectrum of antitumor action. The greatest effect was gained in adenocarcinoma of the lage intestine (strain AKATOL), proventricular cancer (strain PRG) and adenocarcinoma of the mammary gland (strain Ca-755). The terms of survival in mice with leukemia (strain La and L-1210) and ascites hepatoma 22 are increased considerably. In some L-1210 animals the complete cure was noted. Cis-dichlorodiammineplatinum (II) may be effectively combined with sarcolysin. Much greater antitumor effect was obtained on 3 tumor strains (AKATOL, Ca-755 and sarcoma 37) with the combined therapy than with each drug used separately. The histological study of Ca-755 during chemotherapy indicated that immunocompetent cells of the organism play an important role in the mechanism of antitumor action of the platinum complex. This is manifested in the development of intensive lymphohistiocytic reaction around and inside the tumor. A damage to the convoluted tubules of the kidney and intestinal villi is one of the main adverse side-effects of the combination.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cisplatin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Guinea Pigs; Melphalan; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasm Transplantation; Neoplasms, Experimental; Sarcoma, Experimental

The role of cellular and humoral immunity in the localization of blood-borne, bone marrow-derived ADCC effector cells into the T1699 mammary adenocarcinoma was investigated. Administration of ALG before tumor inoculation caused total immunosuppression and resulted in minimal in situ inflammation. ALG treatment started at the time of tumor inoculation suppressed the delayed hypersensitivity response below a detectable level but permitted a significant antibody response. Under these circumstances, the localization of ADCC effector cells into the tumors appeared normal. Similarly, administration of ALG at later stages of tumor growth, where ALG acts as an anti-inflammatory agent, did not interfere with the normal infiltration of ADCC effector cells in situ, although the delayed hypersensitivity response was totally suppressed. When melphalan treatment was used to produce tumor-bearing mice with an intact delayed hypersensitivity response but devoid of a significant antibody response, the drug-treated animals were found to have high levels of ADCC effector cells in situ. These results demonstrate that although the in situ inflammatory reaction appears to be immunologically inflammatory reaction appears to be immunologically dependent, neither the delayed hypersensitivity nor the antibody response is solely responsible for the localization of ADCC effector cells in the T1699 mammary tumor.

Topics: Adenocarcinoma; Animals; Antibody Formation; Antibody-Dependent Cell Cytotoxicity; Antilymphocyte Serum; Dose-Response Relationship, Immunologic; Female; Hypersensitivity, Delayed; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred DBA; Time Factors

In a prospective phase II study, 25 patients with advanced (Duke's D) colorectal adenocarcinoma received 0.25 mg/kg of melphalan orally daily for 4 days every 28 days. There were 17 men and eight women. All patients had measurable areas of known malignant disease which served as objective indicators of the response to chemotherapy. All patients were evaluated for at least two cycles of therapy. Each patient had had previous treatment with 5-fluorouracil and, in addition, 24 of 25 patients had had treatment with methyl-CCNU; all patients had disease progression with both regimens. Toxicity consisted of mild gastrointestinal symptoms and transient leukopenia (wbc count less than 4000/mm3) in nine of 25 (36%) patients and thrombocytopenia (platelet count less than 100,000/mm3) in six of 25 (24%). One of 25 (4%) patients had an objective response for 12 weeks, 15 of 25 (60%) had disease progression, and nine of 25 (36%) remained stable for 2 months. We conclude that melphalan is ineffective for patients with metastatic colorectal carcinoma who have previously failed to respond to both 5-fluorouracil and methyl-CCNU.

Topics: Adenocarcinoma; Adult; Aged; Colonic Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Prospective Studies; Rectal Neoplasms; Semustine

Topics: Adenocarcinoma; Adult; Aged; Bone Marrow; Breast Neoplasms; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Recurrence

Metastatic tumor incidence in BALB/C X DBA/8F1 female mice was examined in the presence and absence of adjuvant chemotherapy. Following surgical removal of spontaneous mammary adenocarcinomas, phenylalanine mustard, adriamycin, and 5-fluorouracil (PAF) were administered at 4, 2, and 50 mg/kg, respectively, once a week for six injections. Recurring tumors and new tumors developing in other breasts over the next 6 months were noted and surgically removed to allow time for originally undetectable pulmonary metastases to develop or to regress completely. This regimen of PAF significantly decreased original tumor recurrences from 58% in controls to 36% in treated mice. New tumor development also was significantly reduced during the 5 weeks of PAF therapy and for 8 weeks thereafter. However, the incidence of pulmonary metastasis was unaffected by the chemotherapy, being 42% in controls and 37% in PAF-treated mice. About 30% of these metastases would have been undetectable at the time of original surgery. The findings stress the importance of developing agents and/or schedules that will specifically affect metastatic cells when administered early to minimal numbers of tumor cells. This system represents a stringent clinimimetic model for evaluating adjuvant chemotherapy in this regard.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary

Combination chemotherapy can produce a rapid and frequent therapeutic effect against advanced endometrial adenocarcinoma regardless of the tumor distribution. A new treatment program is described. Melphalan, 5-fluorouracil, and medroxyprogesterone acetate achieved 6 of 7 objective responses in patients. This result with combination chemotherapy is substantially better than results with single agents or hormones alone and justifies further evaluation of combinations of cytotoxic chemotherapy as part of the initial treatment of choice for patients with advanced endometrial adenocarcinoma.

Topics: Adenocarcinoma; Aged; Drug Therapy, Combination; Female; Fluorouracil; Humans; Medroxyprogesterone; Melphalan; Middle Aged; Uterine Neoplasms

Topics: Adenocarcinoma; Female; Humans; Leukemia, Plasma Cell; Melphalan; Middle Aged; Neoplasms, Multiple Primary; Ovarian Neoplasms

Asaley is an L-leucine derivative of sarcolysin which is more active against some rodent tumors. Studies in the USSR demonstrated activity in patients with ovarian and breast carcinoma, Hodgkin's disease, and multiple myeloma. This study in 73 evaluable patients indicated that an appropriate oral dose for patients with adequate bone marrow is 800 mg/M2/day X 4 days at 5-6 week intervals. The most common toxicities were myelosuppression, nausea, and vomiting. Antitumor activity was observed in 2 of 24 evaluable patients with melanoma, and stabilization of previously progressive disease was observed in patients with adenocarcinoma of the colon, multiple myeloma, lymphoma, breast carcinoma, and thyroid carcinoma. Responses were minimal and of short duration but most of the patients had received extensive prior therapy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Bone Marrow; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Multiple Myeloma; Nausea; Neoplasm Metastasis; Neoplasms; Rats; Remission, Spontaneous; Vomiting

Topics: Adenocarcinoma; Adenocarcinoma, Scirrhous; Age Factors; Aged; Breast Neoplasms; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma

Topics: Adenocarcinoma; Animals; Antilymphocyte Serum; Cell Survival; Cell Transformation, Neoplastic; Cyclophosphamide; Female; Immunosuppression Therapy; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred DBA; Time Factors

We report the serum levels of carcinoembryonic antigen (CEA) in 109 patients with ovarian cancer. Histology, degree of differentiation, and clinical stage influenced the incidence of positive CEA. Although CEA was significantly raised in patients with a variety of tumours, the highest incidence (77 per cent) was found in those with serious cystadenocarcinoma. Nearly all (94 per cent) of the poorly differentiated tumours were associated with a positive CEA result. Serial CEA levels provided a useful guide to management during cytotoxic chemotherapy, rapidly falling levels indicating a favourable tumour response which was reflected clinically. However, only two-thirds of tumours were associated with detectable CEA levels in serum, day-to-day variations in individual serum levels occurred, and CEA levels tended to fall paradoxically during terminal illness. The significance of persistently low levels in the apparent absence of disease was uncertain.

Topics: Adenocarcinoma; Carcinoembryonic Antigen; Cystadenocarcinoma; Cystadenoma; Dysgerminoma; Endometriosis; Female; Follow-Up Studies; Granulosa Cell Tumor; Humans; Melphalan; Mesonephroma; Ovarian Neoplasms; Pregnancy

The role of chemotherapy in influencing tumor-specific immunity to a mouse mammary adenocarcinoma was investigated. By studying different stages of tumor growth we were able to identify several factors important to drug-induced tumor regression: (1) antibody response, (2) delayed hypersensitivity, (3) sensitivity of tumor cells to immune attack and (4) tumor burden. The presence of tumor-specific delayed hypersensitivity and circulating antibody as well as specifically armed monocytes in the tumor mass characterize the T1699 adenocarcinoma. Successful chemotherapy had previously been shown to depend on prior establishment of the above immune responses. Treatment with alkylating agents was marked in all animals by abrogation of a humoral response to the tumor when drug was given early (day 7), and was associated with poor chemotherapeutic results. Later treatment (day 10) was associated with depression of antibody titers only in the minority of animals not responding to drug and prolongation of the delayed hypersensitivity response in all treated animals. Tumors recurring following initial drug-induced regression were marked by lack of delayed hypersensitivity in the host, lack of drug response and suppression of humoral immunity following treatment. Successive passage of cells from these resistant tumors led to decreasing sensitivity to chemotherapy despite established immunity on the part of the host. The selection of tumor cells resistant to immune destruction rather than drug resistance per se appeared to pay a role. Melphalan was thus able to affect both favorably and adversely the immune factors important to drug-induced regression.

Topics: Adenocarcinoma; Animals; Antibodies, Neoplasm; Antibody Formation; Cell Line; Female; Graft Rejection; Hypersensitivity, Delayed; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred DBA; Neoplasm Recurrence, Local; Neoplasm Transplantation; Time Factors; Transplantation, Homologous

Serial carcinoembryonic antigen (CEA) assays were conducted in patients with endocrine-unresponsive prostatic adenocarcinoma who were being treated with multidrug chemotherapy. Changes in CEA correlated with the clinical status of the patient in 70 per cent of the determinations and were more accurate than acid phosphatase in monitoring the response to treatment.

Topics: Acid Phosphatase; Adenocarcinoma; Carcinoembryonic Antigen; Drug Therapy, Combination; Fluorouracil; Humans; Male; Melphalan; Methotrexate; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Vincristine

Topics: Adenocarcinoma; Aged; Anemia, Sideroblastic; Cecal Neoplasms; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Radioisotope Teletherapy; Spinal Neoplasms; Thrombocythemia, Essential

In an attempt to improve the survival rates in women with advanced ovarian adenocarcinoma (abdominal spread), they were treated with sequential therapy. This consisted of operation followed by chemotherapy, second-look exploratory laparotomy, and finally whole-abdomen irradiation. Only those patients who had a complete clinical response to chemotherapy and subsequently underwent a second operation and irradiation were evaluated. Seventy-five per cent of the patients had recurrent cancer within the treated area after sequential therapy was completed. Morever, of four patients with no gross residual cancer after the second operation, three had cancer recurrences within the treated area. It is concluded that methods of treating advanced ovarian adenocarcinoma other than sequential therapy must be found.

Topics: Adenocarcinoma; Chlorambucil; Cyclophosphamide; Dactinomycin; Female; Fluorouracil; Laparotomy; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms

The sensitivity of adenocarcinomas of the stomach to various cytostatic drugs has been tested in short-term incubations. A suspension of single cells and small tissue fragments was prepared. It was used for incubation with the following drugs: melphalan, vinblastine sulphate, amethopterin, and 5-fluoro-uracil. The effect of the cytostatic drugs was measured as the difference in incorporation of labelled precursors in treated tubes and untreated control tubes. The different tumours were found to vary significantly in the their sensitivity. Moreover, a correlation of the effects between melphalan and vinblastine sulphate, and between amethopterin and vinblastine sulphate was observed.

Topics: Adenocarcinoma; Antineoplastic Agents; Cells, Cultured; Depression, Chemical; DNA, Neoplasm; Fluorouracil; Humans; In Vitro Techniques; Melphalan; Methotrexate; Stomach Neoplasms; Thymidine; Tritium; Uridine; Vinblastine

In the present paper a test model was used to examine if human adenocarcinomas of the colon and the stomach are heterogenous as regards the sensitivity to cytosine arabinoside, melphalan, vinblastine sulphate, amethopterin and 5-fluorouracil in vitro. The effects of the five drugs were measured as the differences in incorporation of tritiated thymidine and deoxyuridine in drug-containing tubes and control tubes. It was found, that different parts of eleven colon and five stomach cancers differ significantly in their sensitivity to the same cytostatic treatment in vitro.

Topics: Adenocarcinoma; Antineoplastic Agents; Colonic Neoplasms; Cytarabine; Fluorouracil; Humans; Melphalan; Methotrexate; Stomach Neoplasms; Vinblastine

Topics: Adenocarcinoma; Amides; Androstanols; Animals; Antineoplastic Agents; Cricetinae; Cyclohexanes; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Therapy, Combination; Estradiol; Female; Hydroxyurea; Imidazoles; Mammary Neoplasms, Experimental; Melanoma; Melphalan; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Plasmacytoma; Progesterone; Rats; Sarcoma, Experimental; Triazenes

Topics: Adenocarcinoma; Bleomycin; Carcinoma, Squamous Cell; Castration; Dactinomycin; Estrogens; Female; Humans; Kidney Neoplasms; Male; Melphalan; Nitrosourea Compounds; Phosphorus Isotopes; Plicamycin; Prostatic Neoplasms; Testicular Neoplasms; Urinary Bladder Neoplasms; Urogenital Neoplasms; Vinblastine; Vincristine

Topics: Adenocarcinoma; Alkylating Agents; Animals; Antibodies, Neoplasm; Antibody Formation; Antibody Specificity; Carcinoma 256, Walker; Carcinoma, Squamous Cell; Carrier Proteins; Colonic Neoplasms; Esophageal Neoplasms; Haptens; Hemagglutination Tests; Humans; Immune Sera; Immunization; Immunodiffusion; Immunoelectrophoresis; Melphalan; Rabbits; Rats; Species Specificity

Topics: Adenocarcinoma; Fallopian Tube Neoplasms; Female; Humans; Lung Neoplasms; Melphalan; Middle Aged; Neoplasm Metastasis; Radiography

Topics: Adenocarcinoma; Gastrectomy; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Stomach Neoplasms

Topics: Adenocarcinoma; Autoimmune Diseases; Autopsy; Bone Marrow; Breast Neoplasms; Female; Humans; Immunoglobulin G; Leukemia; Melphalan; Middle Aged; Multiple Myeloma

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Ascites; Chlorambucil; Cobalt Isotopes; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Endometriosis; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms; Radiotherapy, High-Energy; Thiotepa; Vinblastine; Vincristine

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Antineoplastic Agents; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Female; Fluorouracil; Humans; Melphalan; Ovarian Neoplasms

Topics: Adenocarcinoma; Bone Marrow; Centrifugation; Electrophoresis; Humans; Immune Sera; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulins; Male; Melphalan; Middle Aged; Multiple Myeloma; Prostatic Neoplasms; Protein Conformation

Topics: Adenocarcinoma; Animals; Autoradiography; Connective Tissue; Connective Tissue Cells; DNA; Fibroblasts; Male; Melphalan; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Sarcoma, Experimental; Thymidine; Tritium

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma 256, Walker; Dactinomycin; Fluorouracil; Melphalan; Mercaptopurine; Methylthiouracil; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Nitrogen Mustard Compounds; Rats; Sarcoma, Experimental; Time Factors

Topics: Adenocarcinoma; Adult; Aged; Carcinoma; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melphalan; Middle Aged; Parotid Neoplasms; Remission, Spontaneous; Thiotepa

Topics: Adenocarcinoma; Animals; Carcinoma 256, Walker; Chlorambucil; Cyclophosphamide; Melphalan; Mercaptopurine; Mice; Neoplasms, Experimental; Sarcoma, Experimental

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Colonic Neoplasms; Culture Techniques; Disease Models, Animal; DNA; Fluorouracil; Melphalan; Methotrexate; Mice; Spleen

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Cyclophosphamide; Cystadenocarcinoma; Dactinomycin; Female; Fluorouracil; Humans; Mechlorethamine; Melphalan; Ovarian Neoplasms; Thiotepa; Vinblastine

Topics: Adenocarcinoma; Ascitic Fluid; Busulfan; Chromosomes; Female; Humans; Karyotyping; Lymphatic Metastasis; Melphalan; Middle Aged; Neoplasm Metastasis; Ovarian Neoplasms; Peritoneal Neoplasms; Pleural Neoplasms

Topics: Adenocarcinoma; Animals; DNA; Female; Mechlorethamine; Melphalan; Mice; Neoplasms, Experimental; Protein Biosynthesis; RNA; Spleen; Vinblastine

Topics: Adenocarcinoma; Antineoplastic Agents; Chlorambucil; Colchicine; Culture Techniques; Cyclophosphamide; Dactinomycin; Female; Floxuridine; Fluorouracil; Hodgkin Disease; Humans; Melphalan; Mercaptopurine; Methotrexate; Nandrolone; Neoplasms; Nitrogen Mustard Compounds; Norethindrone; Prednisolone; Progesterone; Testosterone; Thiotepa; Uterine Neoplasms; Vinblastine

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Stomach Neoplasms

Topics: Adenocarcinoma; Adenocarcinoma, Papillary; Cystadenoma; Female; Granulosa Cell Tumor; Humans; Melphalan; Neoplasm Metastasis; Ovarian Neoplasms

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma; Cystadenocarcinoma; Cystadenoma; Endometriosis; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms

Topics: Adenocarcinoma; Animals; Fluorides; Injections, Intraperitoneal; Leukemia, Experimental; Leukemia, Lymphoid; Mammary Neoplasms, Experimental; Melphalan; Mice; Phenformin; Sarcoma 37

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Scirrhous; Antibiotics, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Squamous Cell; Culture Techniques; Flavonoids; Fluorouracil; HeLa Cells; Humans; Lung Neoplasms; Melphalan; Mercaptopurine; Methods; Mitomycins; Neoplasms; Rectal Neoplasms; Stomach Neoplasms

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Colonic Neoplasms; Cyclophosphamide; Female; Hodgkin Disease; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasms; Palliative Care; Stomach Neoplasms; Thiotepa

Topics: Adenocarcinoma; Chromium Isotopes; Cobalt Isotopes; Cystadenoma; Dysgerminoma; Female; Gold Isotopes; Granulosa Cell Tumor; Humans; Melphalan; Ovarian Neoplasms; Phosphorus Isotopes; Sertoli-Leydig Cell Tumor; Teratoma; Time Factors

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cyclophosphamide; Female; Fluorouracil; Humans; Hydroxyurea; Mechlorethamine; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Progestins; Thiotepa; Urea; Uterine Cervical Neoplasms

Topics: Adenocarcinoma; Ameloblastoma; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Cyclophosphamide; Ethylenediamines; Facial Neoplasms; Fibrosarcoma; Glioma; Humans; Infusions, Parenteral; Mechlorethamine; Melanoma; Melphalan; Meningioma; Methotrexate; Osteosarcoma; Perfusion; Quinones; Retinoblastoma; Rhabdomyosarcoma; Sarcoma; Thiotepa

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Adult; Female; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Palliative Care

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Carcinoma; Drug Therapy; Humans; Kidney Neoplasms; Kidney Pelvis; Melphalan; Neoplasms; Nephrectomy