pirarubicin and Ovarian-Neoplasms

The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin (06:00h) and cisplatin (18:00h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00h and 21:00h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Cycle; Chronotherapy; Circadian Rhythm; Cisplatin; Doxorubicin; Endometrial Neoplasms; Female; Floxuridine; Genital Neoplasms, Female; Humans; Kidney Neoplasms; Male; Ovarian Neoplasms; Prostatic Neoplasms; Rats; Urinary Bladder Neoplasms; Urogenital Neoplasms

A 40-year-old woman, who had suffered from AML (M1) in 1983, developed ovarian cancer (stage IIIc) in December 1996 after long-term remission. She underwent surgical resection of the cancer, 10 courses of standard chemotherapy and tandem PBSCT (total dose: CBDCA 6,750 mg, CDDP 200 mg, CPA 16,000 mg, THP-ADR 450 mg). After receiving the last course of chemotherapy in June 1998, she was referred to our hospital in September 1998 because of pancytopenia. Laboratory findings showed pancytopenia with 34% leukemic cells, which were positive for alpha NBE and negative for POX and CAE. Surface-marker analysis of the leukemic cells showed positivity for CD11c, CD33, CD56, and DR, and chromosome analysis revealed 47, XX, +8. The patient was diagnosed as having AML (M5a), and received induction therapy consisting of IDR and Ara-C, which led to complete remission. As she had not received etoposide, this case was thought to have been therapy-related leukemia due to the platinum agents used for treating the ovarian cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Leukemia, Myeloid; Neoplasms, Second Primary; Ovarian Neoplasms

Nineteen patients diagnosed with peritoneal carcinomatosis were treated by in-home chemotherapy over a period of four years from August, 1990 to July, 1994. Primary diagnoses of the four male and 15 female patients included 12 cases gastric cancer (four males, eight females), five cases of ovarian cancer, one case (female) of appendicular cancer, and one case (female) of breast cancer. In addition to oral administration of UFT-E and 5'-DFUR, chemotherapy included weekly intravenous injection of a massive dose of 5-FU (1,000 mg/m2), subselective intraaortic infusion and intraperitoneal infusion using a reservoir. These methods were used individually and in combination. The drugs used included 5-FU, CBDCA, CPA, THP, and EPIR. Subselective intraaortic infusion was performed by low dose continuous infusion using the Baxter infusor multiday type. Six gastric cancer patients lived normally for over one year, while four died in less than a year. All ovarian and appendicular cancer patients were CR, the breast cancer patient was PR. Ten patients continued working at their jobs while receiving at home chemotherapy treatments. Diuretics were used to alleviats ascites. Although there were no side effects on digestive organs, 5-FU and CBDCA were mixed with 100 mg hydrocortisone in the infusor to improve cachexia, and promote appetite and activity. Bone marrow suppression was very slight at these dosages, and weekly checkups were adequate. The at-home rate (number of days at home/entire period since onset) of all patients was 78%.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Home Care Services, Hospital-Based; Home Infusion Therapy; Humans; Infusion Pumps, Implantable; Infusions, Parenteral; Male; Middle Aged; Ovarian Neoplasms; Peritoneal Neoplasms; Stomach Neoplasms

Although 50%-80% of patients with advanced ovarian cancer demonstrate an objective response after platinum-based chemotherapy, a majority of these patients will ultimately experience a relapse of their disease. Effective second-line treatment for these patients is of the most importance. We performed a phase II study with cisplatin and pirarubicin (each drug 50 mg/m2 i.v. every 28 days) in 17 patients with relapsed or persistent ovarian carcinoma. All patients had received platinum-containing primary chemotherapy. Overall survival from the time of diagnosis was 38.3 months (45.3 months in relapsed ovarian carcinoma and 28.3 months in ovarian carcinoma persisting after primary chemotherapy). Survival from entrance into the study was 13.0 months (14.2 months in relapsed disease and 11.2 months in refractory disease). Time to progression was 10.3 months. An objective response was observed in 4 patients and another 3 patients had stable disease. Major toxicity consisted of emesis (grade III/IV in 60/64 courses) and myelosuppression WHO grade III/IV in 15 courses. Neurotoxicity occurred in 3 patients and nephrotoxicity in 1 patient. Alopecia occurred in 12 patients. Tachycardia and other low-grade heart toxicities were observed after 5 courses. Dose reduction was necessary because of severe myelosuppression in 4 courses and because of nephrotoxicity in 1 course. Delay of subsequent chemotherapy courses for more than 7 days was necessary after 13 courses and was always due to myelosuppression. The dose-limiting toxicity of combination chemotherapy with cisplatin and pirarubicin is myelosuppression. Response and survival rates are superior in patients with relapsed disease compared to patients with resistant ovarian carcinoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cisplatin; Doxorubicin; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms

From 1986 to 1990, a multicentric phase II study was conducted with pirarubicin, a new semi-synthetic anthracyclin[4'-O-tetrahydropyranyl-adriamycin (THP)]. 87 patients with advanced gynaecological cancers were treated: epidermoid cervical carcinoma (n = 31), adenocarcinoma of the endometrium (n = 28) and ovarian adenocarcinoma (n = 28). THP was administered by short intravenous infusion, for 3 consecutive days, every 3 weeks. The initial dose of THP was 25 mg/m2 day (25% of patients) which was then reduced to 20 mg/m2 day. The average number of courses was 3.7 (range 1-10). The cumulative THP dose was 180 mg/m2 (range 56-594) in cervix and endometrial tumours and 121 mg/m2 (range 58-425) in ovarian tumours. Myelosuppression was the major observed toxicity with grade 3-4 leukopenia and thrombocytopenia in 62 and 19% of the patients, respectively. Severe general complications occurred in 6% of the patients with three fatalities due to infections. Gastro-intestinal side-effects were frequent and usually mild (7% of grade 3 vomiting). 48% of the patients showed alopecia, which was complete in 9 cases (10%). 3 patients experienced cardiac events. No significant antitumoral activity was observed in patients who had failed to respond to previous chemotherapy. Promising antitumoral activity was noticed in untreated cervico-uterine carcinomas with 19% partial responses and 12% complete responses (CR). THP activity was lower in endometrial carcinomas (9.5% CR). Results were found to be negligible in ovarian cancer patients, most of them being refractory to previous chemotherapy containing an anthracyclin compound. On the basis of these results, the definite role of THP in gynaecological cancers deserves to be studied in more favourable programmes (e.g. in combined protocols as first-line chemotherapy).

Topics: Adenocarcinoma; Adult; Aged; Alopecia; Antineoplastic Agents; Doxorubicin; Endometrial Neoplasms; Female; Humans; Leukopenia; Middle Aged; Ovarian Neoplasms; Thrombocytopenia; Uterine Cervical Neoplasms; Vomiting

The efficacy and toxicity of the new anthracycline, 4'-0-tetrahydropyranyl doxorubicin (THP) (50 mg/m2 intravenous [IV] bolus) in association with cisplatin (100 mg/m2 IV as a 4-hour infusion) was assessed in 31 patients with advanced ovarian carcinoma. Twenty-eight patients were assessable for toxicity among whom 25 were assessable for response (International Federation of Gynecology and Obstetrics [FIGO] stage IIIa, four patients; IIIb, 15 patients; IV, six patients). Nine patients had received prior treatment. Patients were randomized to receive schedule (sch) A (THP at 6 hours, then cisplatin from 16 to 20 hours) or sch B (THP at 18 hours, then cisplatin from 4 to 8 hours). Sch A was hypothesized as less toxic since THP was best tolerated in the late rest span and cisplatin near the middle of the activity span in experimental studies. The rate of clinical complete response (CR) was 52%, that of partial response (PR) was 12%, and the overall clinical response rate (CR plus PR) was 64% (sch A, 73%; sch B, 57%). Median progression-free survival and survival times were, respectively, 10 and 19 months. Of 12 patients in clinical CR evaluated at second-look laparotomy, four had a pathological CR (33%), and three had microscopic residual disease (MD). The overall rate of pathological CR was 16%. Sch A was associated with less neutropenia (P = .10), thrombocytopenia (P less than .01), anemia (P less than .01), and renal toxicity (P less than .05) than sch B. Of four patients withdrawn for toxicity, three were on sch B (one death). Mean dose intensities (DIs) of THP and cisplatin, respectively, decreased by 30% and 47% over the five initial courses. Such decrease was significantly more pronounced for sch B than for sch A in previously untreated patients (P from 2-way analysis of variance [ANOVA] less than .01). THP-cisplatin is active against advanced ovarian cancer, and its toxicities can be significantly decreased by dosing THP in the early morning and cisplatin in the late afternoon as compared with THP in the evening and cisplatin the next morning.

Topics: Antineoplastic Combined Chemotherapy Protocols; Circadian Rhythm; Cisplatin; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Neoplasm Staging; Ovarian Neoplasms; Randomized Controlled Trials as Topic; Remission Induction; Survival Rate

Lipoparticles are the core-shell type lipid-polymer hybrid systems comprising polymeric nanoparticle core enveloped by single or multiple pegylated lipid layers (shell), thereby melding the biomimetic properties of long-circulating vesicles as well as the mechanical advantages of the nanoparticles. The present study was aimed at the development of such an integrated system, combining the photodynamic and chemotherapeutic approaches for the treatment of multidrug-resistant cancers.. For this rationale, two different sized Pirarubicin (THP) loaded poly lactic-co-glycolic acid (PLGA) nanoparticles were prepared by emulsion solvent evaporation technique, whereas liposomes containing Temoporfin (mTHPC) were prepared by lipid film hydration method. Physicochemical and morphological characterizations were done using dynamic light scattering, laser doppler anemometry, atomic force microscopy, and transmission electron microscopy. The quantitative assessment of cell damage was determined using MTT and reactive oxygen species (ROS) assay. The biocompatibility of the nanoformulations was evaluated with serum stability testing, haemocompatibility as well as acute in vivo toxicity using female albino (BALB/c) mice.. The mean hydrodynamic diameter of the formulations was found between 108.80 ± 2.10 to 405.70 ± 10.00 nm with the zeta (ζ) potential ranging from -12.70 ± 1.20 to 5.90 ± 1.10 mV. Based on the physicochemical evaluations, the selected THP nanoparticles were coated with mTHPC liposomes to produce lipid-coated nanoparticles (LCNPs). A significant (p< 0.001) cytotoxicity synergism was evident in LCNPs when irradiated at 652 nm, using an LED device. No incidence of genotoxicity was observed as seen with the comet assay. The LCNPs decreased the generalized in vivo toxicity as compared to the free drugs and was evident from the serum biochemical profile, visceral body index, liver function tests as well as renal function tests. The histopathological examinations of the vital organs revealed no significant evidence of toxicity suggesting the safety and efficacy of our lipid-polymer hybrid system.

Topics: Animals; Cell Death; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Liberation; Female; Humans; Inhibitory Concentration 50; Kinetics; Lipids; Liposomes; Liver Function Tests; Mesoporphyrins; Mice; Mice, Inbred BALB C; Nanoparticles; Ovarian Neoplasms; Photochemotherapy; Polylactic Acid-Polyglycolic Acid Copolymer; Reactive Oxygen Species; Toxicity Tests, Acute

We have previously demonstrated that the cytotoxicity of anthracyclines, pirarubicin (THP) and doxorubicin (DOX), is partially dominated by their intracellular amounts, which depend on the uptake efficacy of transporter(s). To clarify their transport mechanism, we examined whether or not Na+/nucleoside cotransporter (CNT) is involved in the uptake of THP by M5076 cells.. Expression of the CNT isoforms was determined by reverse-transcription PCR. We used two cell lines, intact M5076 and CNT2-transfected Cos-7 cells, to characterize the uptake of THP and [3H]uridine.. The mRNA for CNT2, but not that for CNT1 or CNT3, was expressed in M5076 cells, and [3H]uridine uptake by the cells required a Na+ gradient as a driving force. THP uptake by M5076 cells depended on a Na+ gradient, and furthermore, formycin B and AZT had cis-inhibitory and trans-stimulatory effects on the uptake. The efflux of [3H]uridine from M5076 cells was stimulated by the addition of THP extracellularly, which constituted definite evidence of CNT-mediated uptake of THP. However, THP uptake by CNT2 transfectant was almost the same as that by mock cells, indicating that an unidentified CNT isoform contributes to THP uptake by M5076 cells, this being supported by the differences in transport characteristics of [3H]uridine between M5076 and CNT2-transfected cells.. THP is partially taken up into M5076 cells via a novel Na+-dependent transport system common to nucleosides.

Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Female; Mice; Nucleoside Transport Proteins; Ovarian Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Sodium; Transfection; Tumor Cells, Cultured; Uridine

A 5-year-old girl presented with a painful abdominal mass. Abdominal magnetic resonance imaging (MRI) showed 3 separate masses. Tumor markers including lactate dehydrogenase (LDH), cancer antigen-125 (CA-125), beta-subunit of human chorionic gonadotropin (beta-hCG) and neuron-specific enolase (NSE) were elevated. At operation, the main tumor arose from the left ovary and was associated with torsion, whereas the other lesions were lymph node metastases. A salpingo-oophorectomy was performed. Histopathologic examination indicated that the tumor was a dysgerminoma. Immunohistochemicallly, the cells were positive for NSE and placental alkaline phosphatase (PALP) but were negative for CA-125, beta-hCG, S-100, glial fibrillary acidic protein, and vimentin. The elevated serum levels of tumor markers improved dramatically after the operation and chemotherapy.

Topics: Alkaline Phosphatase; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bleomycin; CA-125 Antigen; CA-19-9 Antigen; Carboplatin; Child, Preschool; Chorionic Gonadotropin, beta Subunit, Human; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Dysgerminoma; Female; Humans; Isoenzymes; L-Lactate Dehydrogenase; Neoplasm Proteins; Ovarian Neoplasms; Ovariectomy; Phosphopyruvate Hydratase; Torsion Abnormality; Vinblastine

To evaluate the validity of administration of paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with gynecologic cancer, we explored the efficacy and safety of these regimens. From October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin with or without THP-ADR pursuant to the chart we prepared originally as first line chemotherapy in patients with gynecologic cancer. Eleven elderly patients (age > 70 years) and 62 younger patients (age < 70 years) were entered into the present study. Paclitaxel was administered as a 3-hour intravenous (i.v.) infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over 60 minutes at dosages of area under the curve (AUC) 3 to 5, administered intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p = 0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly patients receiving the regimen including paclitaxel and carboplatin with THP-ADR. The overall response rates were equivalent among elderly and younger patients (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin without THP-ADR was applied safely to elderly patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Doxorubicin; Drug Administration Schedule; Endometrial Neoplasms; Female; Genital Neoplasms, Female; Humans; Leukopenia; Middle Aged; Neutropenia; Ovarian Neoplasms; Paclitaxel; Retrospective Studies; Taxoids; Thrombocytopenia; Uterine Cervical Neoplasms

We sought to determine whether the de novo resistance of M5076 ovarian sarcoma cells, which show sensitivity to pirarubicin (THP), to doxorubicin (DOX) is due to differences in the transport characteristics between THP and DOX, and the results were compared with those for drug-sensitive Ehrlich ascites carcinoma cells.. The in vitro cytotoxicity of the drugs was assessed by means of the tetrazolium dye assay. Transport experiments were performed by the rapid centrifugation method.. In an in vitro cytotoxicity experiment, M5076 cells showed lower sensitivity to DOX than to THP, and the cytotoxicity of THP and DOX toward M5076 cells was lower than toward Ehrlich cells, and these results were similar to those of an in vivo experiment. This was due to the much lower expression of topoisomerase II in M5076 cells than in Ehrlich cells. The amount of intracellular DOX was found to be significantly lower than that of THP in both cell types, and furthermore, little free intracellular DOX was observed in M5076 cells, indicating that the low sensitivity of M5076 cells to DOX was partially a result of the low amount of intracellular DOX. There was no difference in the efflux rate, but there was an apparent difference in the uptake efficiency of the carrier between THP and DOX.. These findings suggest that the cytotoxicities of THP and DOX toward M5076 and Ehrlich cells depend, at least in part, on the uptake efficiency of the carrier.

Topics: Animals; Antibiotics, Antineoplastic; Biological Transport; Carcinoma, Ehrlich Tumor; Cell Survival; Dinitrophenols; Doxorubicin; Female; Humans; Kinetics; Mice; Ovarian Neoplasms; Sarcoma; Temperature; Time Factors; Tumor Cells, Cultured

We have compared the membrane transport and antitumor activity of pirarubicin with those of doxorubicin in M5076 ovarian sarcoma, which exhibits low sensitivity to doxorubicin. Pirarubicin was rapidly taken up by M5076 cells and the intracellular concentration of pirarubicin reached more than 2.5-fold that of doxorubicin. In terms of the 50% cell growth-inhibitory concentration in vitro, pirarubicin was more effective than doxorubicin. Thus, the intracellular concentration influenced the cytotoxicity of these anthracycline agents. On comparison of the nuclear uptake of pirarubicin and doxorubicin, the nucleus/cell ratio of pirarubicin was found to be about 40%, whereas that of doxorubicin reached more than 80%. As the intranuclear concentration of pirarubicin is dependent on nuclear transport, the increases in not only cell membrane transport, but also nuclear membrane transport contributed to the enhancement of the efficacy of pirarubicin. In M5076 solid tumor-bearing mice, pirarubicin reduced the tumor weight to 60% of the control level, although doxorubicin had no effect. These results were supported by the intracellular uptake of pirarubicin. Moreover, theanine, which inhibited the pirarubicin efflux from M5076 cells, increased by 1.3-fold the pirarubicin concentration in the tumor and enhanced the therapeutic efficacy of pirarubicin 1.7-fold. In conclusion, our results suggest that an increase in the concentration of an anthracycline derivative in tumor cells due to alteration of cell membrane transport results in enhancement of the antitumor activity.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biological Transport; Cell Division; Cell Membrane; Cell Nucleus; Doxorubicin; Drug Interactions; Female; Glutamates; Male; Mice; Neoplasm Transplantation; Ovarian Neoplasms; Sarcoma, Experimental; Tea; Tumor Cells, Cultured

The effect of the anthracycline analogue, pirarubicin, on cardiac function was examined. One hundred and four patients with gynecologic malignancies were treated with 40-50 mg/body THP ADM every 3 to 4 weeks by iv bolus injection. Three out of 104 cases that had developed cardiac failure received more than 1,500 mg. One case receiving 1,340 mg developed cardiac failure and expired 3 years after completion of treatment for malignancy. From the above experience, it is concluded that the MTD of pirarubicin seems to be 1,500 mg/body or 1,100 mg/m2.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Doxorubicin; Drug Administration Schedule; Electrocardiography; Female; Heart; Humans; Middle Aged; Myocardium; Ovarian Neoplasms; Uterine Neoplasms

A patient with navel metastasis from ovarian carcinoma was treated by immunotherapy and neo-adjuvant intraarterial infusion chemotherapy (OK-432 i.c., VP-16 25 mg/body x 10 days po, CDDP 100 mg/m2 iA, CPM 200 mg x 3 days/body i.v., THP 50 mg/m2 iA). Maximal blood concentration of THP was 1.081 micrograms/ml at 1 hour intraarterially and 0.091 microgram/ml at 2 hour intravenously. THP concentration of arteria is ten times higher than that of venous. And the area under the curve (AUC) of THP is 3.46 micrograms/ml/hr intraarterially and 0.43 microgram/ml/hr at intravenous. Two courses of the neo-adjuvant intraarterial chemotherapy were done. One month after, the first operation was performed. Each tissue platina concentration is 9.72 micrograms/ml is 9.72 micrograms/cm3 uterus cervix, 7.10 micrograms/cm3 uterus corporis, 5.72 micrograms/cm3 left ovarium, 2.64 micrograms/cm3 right ovarium, 0.52 microgram/cm3 paraaortic lymph node. After the immuno-chemotherapy, the metastatic tumor appeared remarkably smaller and the main tumor regained normal size and we achieved the optimal operation successfully. This patient was treated with double platina chemotherapy by intraperitoneal infusion using implantable reservoir access after the first operation (VP-16 200 mg/m2 i.p. D1, CDDP 100 mg/m2 ip D1, CBDCA 300 mg/m2 i.v. D3). This patient can keep the state of cytological complete remission for more than four months after the second look operation. Now she continues maintenance immuno-chemotherapy from a home doctor.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Immunotherapy; Infusion Pumps, Implantable; Neoplasm Staging; Ovarian Neoplasms; Picibanil; Remission Induction

We analysed the in vitro sensitivity of 50 fresh gynecologic cancer specimens to the new anthracycline-analogue pirarubicin (Pira). Nine endometrial and cervical tumors were excluded from the evaluation in this study. The in vitro sensitivities of 41 ovarian cancer specimens to Pira were evaluated with the adenosine triphosphate chemosensitivity assay (ATP-CSA). The results were compared to the sensitivity of drugs used in gynecologic oncology: Adriamycin, cisplatin, and the metabolite of cyclophosphamide, 4-hydroxycyclophosphamide (4-HC). Sensitivity (S) is defined as > or = 70%, partial sensitivity as 50-69% ATP decrease compared to controls at 20% of the peak plasma concentration. In vitro response is defined as S + PS. Twenty-two primary ovarian tumors were assayed, with 77% response to Pira, 12% to Adriamycin, 29% to cisplatin, and 38% to 4-HC. In 19 recurrent ovarian tumors, Pira showed 53% response; Adriamycin, 25%; cisplatin, 8%; and 4-HC, 67%. The in vitro data are partly consistent with reported data from the literature. Pira reveals a significantly higher degree of cytotoxicity compared to the three drugs listed above. The IC50 of Pira is less than 20% of the peak plasma concentration achievable in patients and is significantly lower compared with the IC50s of other drugs. We conclude from our in vitro data that Pira is more active than Adriamycin, cisplatin, and 4-HC.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Screening Assays, Antitumor; Female; Humans; In Vitro Techniques; Ovarian Neoplasms; Recurrence

One case of pulmonary metastasis of leiomyosarcoma responsive to CTP therapy was reported. The patient was a 44-year-old woman who had undergone total simple hysterectomy for uterine myoma 6 years before. Five years after the operation she underwent ovariectomy for ovarian tumor. Based on the histopathological findings, she was diagnosed to have leiomyosarcoma. One year later the patient was referred to use because of pulmonary metastasis. After admission to our hospital CTP therapy was started. Disappearance of the metastatic lesion was demonstrated by the chest X-ray findings at the end of five courses of treatment.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Leiomyosarcoma; Lung Neoplasms; Ovarian Neoplasms

Surgery was attempted in a case of stage IV ovarian cancer with a hepatic metastatic lesion measuring 119 x 96 mm. However, radical surgery was impossible and the operation ended up as no more than exploratory laparotomy. Before closing, Cisplatin 100 mg and Etoposide 200 mg were instilled into the intraperitoneal cavity. Two courses of systemic chemotherapy with PAC (Cisplatin 50 mg, Pirarubicin 40 mg, Cyclophosphamide 400 mg) were instituted. To examine shrinkage of the hepatic metastasis and the peritoneal tumors, A "Second look" operation was conducted. Abdominal simple total hysterectomy, bilateral salpingo-oophorectomy, omentectomy and partial sigmoidectomy resulted in no residual lesions in the peritoneal cavity with the exception of the hepatic metastatic lesion (69 x 57 mm). Two additional courses of PAC therapy were administered after the "Second look" operation. The hepatic metastatic lesion shrank to 45 x 41 mm; a decrease of 83.8% compared to the pre-therapy in size. Liver function tests and tumor chemical markers (TPA, CA 125, SLX) revealed decreased values that were consistent with a tumor size reduction. Good PR was achieved with only a systemic chemotherapy; i.e., without resorting to local injections of chemotherapeutic agents into the liver.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Cystadenocarcinoma; Doxorubicin; Female; Humans; Liver Neoplasms; Middle Aged; Ovarian Neoplasms; Remission Induction

We have studied the pharmacokinetics and metabolism of pirarubicin (4'-O-tetrahydropyranyldoxorubicin) in six patients included in an EORTC phase II study. Pirarubicin was injected as an i.v. bolus of 5 min on 3 consecutive days at a dose of 20 mg/m2 per day. Blood samples were collected at regular times after each injection. Urine was collected over 12 h periods for 3 days and then over 24 h periods. Pirarubicin and metabolites were extracted on Sep-pak cartridges, and analyzed by HPLC with fluorometric detection. Unchanged pirarubicin followed three similar plasma concentration curves, which could be fitted by a two-compartment model with successive half-lives of 22.0 min and 12.7 h. Total plasma clearance of the drug was 90 l/h/m2 and total volume of distribution 1380 l/m2. Doxorubicin was the main metabolite in plasma after an injection of pirarubicin; its concentration was lower than that of pirarubicin but progressively increased from day to day and exceeded the level of pirarubicin 8 h after the 3rd injection of the drug until the end of the blood sampling. Pirarubicinol and doxorubicinol were also metabolites of pirarubicin in plasma; pirarubicinol followed similar plasma concentration curves during the 3 days of treatment whereas doxorubicinol progressively increased from day to day. Total urinary excretion represented about 6% of the dose injected. The same metabolites as in plasma were found in urine. Whereas the total amount of pirarubicin and pirarubicinol was the same in urine during the 24 h after each injection, the amounts of doxorubicin and doxorubicinol excreted increased from day to day, so that doxorubicin became progressively the main compound in urine after the end of the treatment. The progressive accumulation of pirarubicin metabolites (doxorubicin and doxorubicinol) after the repetitive injections of pirarubicin are probably due to the protracted half-lives of these compounds as compared to that of pirarubicin.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Doxorubicin; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Uterine Neoplasms

The in vitro evaluation of anticancer drug efficacy was performed using the human tumor clonogenic assay developed by Hamburger and Salmon, and correlation between the in vitro and clinical efficacy was analyzed retrospectively. The in vitro colony assay method used in this study was a minor modification of the above method. Thirty-two out of forty-eight samples from patients with ovarian cancer formed more than five colonies per plate on in vitro colony assay. The median plating efficiency was 0.06% (range 0.02-1.3%) and the median colony count per plate was 279 (range: 8-4,000). With regard to colony formation of ovarian cancer according to the source of the specimen, the colony-forming rate of solid tumor was high (72%) as compared with 63% for ascites and 43% for pleural effusion. In vitro chemosensitivity was defined as more than a 50% decrease in colony formation and the rates for standard drugs on ovarian cancer were as follows: adriamycin (0.04 micrograms/ml) 29%, bleomycin (0.1 micrograms/ml) 24% cisplatin (0.2 micrograms/ml) 31%, 5-FU (1.0 micrograms/ml) 22%, hexamethylmelamine (1.0 micrograms/ml) 19%, L-PAM (0.4 micrograms/ml) 44%, mitomycin C (0.1 micrograms/ml) 38% and THP-adriamycin (0.5 micrograms/ml) 36%. A group of patients who had not been exposed to any anticancer drug showed higher sensitivity in vitro as compared with a group of patients who had received prior chemotherapy (35% vs 22%, p less than 0.05). Correlation between in vitro drug sensitivity and clinical responses in patients treated with the same drugs were analysed retrospectively. In all twenty cases, two were true positive cases (29%), while in ten cases, the results were true negative (77%), The overall predictive accuracy was 60%. In conclusion, ovarian cancer cells can form colonies well when the soft agar method is used and this assay method is suitable for the evaluation of various anticancer drugs in vitro.

Topics: Altretamine; Antineoplastic Agents; Bleomycin; Cell Division; Cells, Cultured; Cisplatin; Colony-Forming Units Assay; Doxorubicin; Drug Evaluation, Preclinical; Female; Humans; Ovarian Neoplasms; Tumor Stem Cell Assay

We conducted a joint phase II study in 76 patients with gynecological cancer (42 patients with ovarian cancer, 22 patients with cervical cancer, 10 patients with endometrial cancer and 2 patients with vaginal cancer). The response rate was 25.0% in the patients with ovarian cancer, 13.3% in those with cervical cancer, and 28.6% in those with endometrial cancer. The overall response rate was 23.1%. When the patients were classified according to dose schedules, the highest response rate was obtained in the group administered THP-ADM at a dose of 60 mg per body by single i.v. injection at 3-week intervals. Such side effects as myelosuppression and gastrointestinal disturbances were observed, but alopecia, a marked side-effect of ADM administration, was mild, and no cardiac toxicity was seen in any of the patients.

Topics: Adult; Aged; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Genital Neoplasms, Female; Humans; Middle Aged; Ovarian Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms; Vaginal Neoplasms

A phase II clinical trial of a new anthracycline, 4'-O-tetrahydropyranyladriamycin (THP-ADM), was performed in thirty-one patients with advanced malignant tumors refractory to standard chemotherapies. The dosage of THP-ADM was 40 mg/m2 by iv bolus injection repeated every 3 weeks. Of 3 evaluable patients with non-Hodgkin's lymphoma, one achieved partial remission. A minor response was noted in one out of 7 patients with gastric cancer and one out of 5 patients with ovarian cancer. Leukopenia less than 4 X 10(3)/cmm and thrombocytopenia less than 100 X 10(3)/cmm were seen in 81% and 19% of cases, respectively. Mild gastrointestinal toxicities including nausea and vomiting and anorexia were observed in about one third of the patients. Mild hair loss occurred in 2 patients (6%). No ECG abnormalities on clinical sign of cardiotoxicity were seen.

Topics: Aged; Breast Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Stomach Neoplasms

4'-0-tetrahydropyranyladriamycin hydrochloride (THP-ADM) is a new anthracycline derivative. The antitumor activity of THP-ADM was tested on 51 human tumor samples representing ten different tumor types in in vitro colony assay method. Tested tumors were: 26 cases of ovarian cancer, 8 cases of breast cancer, 6 cases of colorectal cancer, 3 cases of endometrial cancer, 2 cases each with gastric cancer and sarcoma, and another 4 cases. An in vitro colony assay was done in soft agar as described by Hamburger & Salmon. The criteria for in vitro sensitivity was defined as a 70 percent or greater reduction in the number of colonies after a 1-h exposure to drugs. The selected concentrations of THP-ADM for assay were 0.05, 0.5, and 1.0 micrograms/ml. The sensitivity rates for THP-ADM in each dose were: 0.05 micrograms/ml (7/19, 37%), 0.5 micrograms/ml (10/51, 20%), and 1.0 micrograms/ml (12/19, 63%). In vitro sensitivity of adriamycin (0.04 micrograms/ml) was simultaneously tested in 49 cancer patients. Five out of 25 ovarian cancer patients (20%) showed responses to adriamycin and an overall response rate was 12% (6/49). These data indicate that THP-ADM has an antitumor activity against various cancers and it is comparable to that of adriamycin.

Topics: Antineoplastic Agents; Cells, Cultured; Colony-Forming Units Assay; Doxorubicin; Drug Evaluation; Female; Humans; Ovarian Neoplasms; Tumor Stem Cell Assay

THP-ADM is a new antitumor antibiotic which belongs to the anthracycline group. This agent was administered to 42 histology proven various malignant disease patients with a schedule of 60-80 mg per body (40-55 mg per m2) iv bolus, every three weeks. THP-ADM administration revealed mild upper GI toxicity (vomiting 19%, stomatitis 21%) and leukopenia (less than 2,000 per mm3) in 80% and thrombocytopenia (less than 60,000 per mm3) in 38% with good rebound. There was no signs or symptoms of cardiac failure including the patient who had received 740 mg per body (500 mg per m2). Definite response (CR, PR) was observed in ovarian carcinoma 4/11, cervix carcinoma 2/7, breast carcinoma 1/6, malignant lymphoma 5/5 and mesothelioma 1/2. Furthermore, some response (MR) was observed in lung metastasis from endometrial carcinoma 2/4, and stomach carcinoma 1/3. The above indicated usefulness of this agent and further study should be continued, especially a controlled study with adriamycin.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Doxorubicin; Drug Evaluation; Female; Humans; Lymphoma; Male; Mesothelioma; Middle Aged; Ovarian Neoplasms; Sarcoma; Stomach Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms