pirarubicin and Colonic-Neoplasms

Eighty patients with measurable metastatic colon or renal cancer, melanoma, or sarcoma entered these Phase II studies. A dose of 25 mg/m2/day of Pirarubicin (THP) for 3 consecutive days every 4 weeks for the first patients, and then 20 mg/m2/day for 3 days every 3 weeks was given by i.v. push. These patients received 225 cycles for a median cumulative dose of 165 mg/m2 (range: 55-630). The mean number of cycles given was 2.8 (range: 1-8). Only 3 partial responses and 18 stable disease (22%) were observed. Hematologic toxicity was the main problem; it was responsible for one death and a 19% and 44% incidence of grade 3 and 4 WHO neutropenia, respectively. Alopecia was rare (4%). Chemotherapy was discontinued in three cases because of suspicion of cardiac toxicity, but only one patient had a significant drop in left ventricular ejection fraction at a cumulative THP dosage of 120 mg/m2. A lack of efficacy in renal and colon cancer and melanoma was presupposed and confirmed by these trials. Due to pretreatment with anthracycline in most patients, definite evaluation of THP in soft tissue sarcoma could not be given.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Carcinoma; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Humans; Kidney Neoplasms; Melanoma; Middle Aged; Sarcoma; Soft Tissue Neoplasms

Little evidence is known from experimental research for intraoperative hyperthermic intraperitoneal chemotherapy. This study was to investigate the effect of hyperthermic chemotherapy on gastrointestinal cancer cells in vitro and explore the possible factors which may affect this method.. Gastric cancer cell line MGC-803 and intestinal cancer cell line HCT-116 were chosen. Cells were treated with different drugs, temperatures and duration. Cell viability and growth were measured by MTS-PMS assay. The morphology of the cells was observed under a microscope.. Significant synergistic effect was observed when the two cancer cell lines were treated with 5-FU, MMC, DDP and THP in combination with elevated hyperthermia from 41 degrees C to 45 degrees C compared with control group (P<0.01). The strongest effect was achieved at 45 degrees C, which the inhibitory effects of these four drugs were 61.7%, 79.2%, 88.7%, 94.7% on MGC-803 and 76.4%, 78.7%, 77.8%, 91.7 on HCT-1116, respectively. The inhibitory effect demonstrated a time and dose-dependent manner in HCT-116 cells within a certain period of time. The effect revealed a flat curve after 90 min when HCT-116 was treated with 43 centigrade. THP had the strongest effect at any conditions among all tested drugs (P<0.01). Either simple thermotherapy or chemohyperthermia displayed considerable killing effects on cancer cells which were confirmed by microscope observation. And a great deal of dead cells were observed when treated with chemohyperthermia.. DDP or MMC reveals relatively satisfactory antitumor effects with the optimal temperature of 43-45 degrees C. Taken practical application into consideration, 60 min may be selected in clinical use. Synergistic antitumor effects of THP in combination with hyperthermia were prior to 5-FU, DDP or MMC, which deserve further clinical research.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Cell Line, Tumor; Cell Survival; Cisplatin; Colonic Neoplasms; Combined Modality Therapy; Doxorubicin; Fluorouracil; Humans; Hyperthermia, Induced; Mitomycin; Stomach Neoplasms

Free malignant cells, which are frequently detected in the washing liquid from the peritoneal cavity before and after resection of human colorectal cancer, are suspected to cause recurrent peritoneal cancer. We carried out an experimental study to compare the prophylactic efficacy of washing the peritoneum with several anticancer drugs and the antiseptic povidone-iodine against the development of peritoneal carcinomatosis from colonic origin in rats and nude mice. The in vitro anticancer activity of a short, 15-minute exposure of pirarubicin, doxorubicin, 5-fluorouracil, cisplatin, mitomycin C, and 1% povidone-iodine was first evaluated by an MTT assay on DHD/K12/PROb rat and LS174T human colon cancer cells. For the in vivo experiments, BDIX rats were inoculated intraperitoneally (i.p.) with 1 x 10(6) DHD/K12/PROb cells followed by peritoneal scarring and a colocolic anastomosis. A 15-minute peritoneal washing with the anticancer drugs or povidone-iodine was then performed. Nude mice were i.p.-inoculated with 1 x 10(7) LS174T human cells and treated 2 hours later with i.p. pirarubicin. Only pirarubicin, mitomycin C, and povidone-iodine were fully cytotoxic in vitro against DHD/K12/PROb rat colon cancer cells. In contrast to pirarubicin and povidone-iodine, mitomycin C was not completely active against LS174Tcells. In vivo, pirarubicin cured DHD/K12/PROb-inoculated rats, even at the site of the peritoneal scarring and intestinal anastomosis. i.p. pirarubicin prevented the development of peritoneal carcinomatosis and liver metastasis in LS174T-inoculated mice. i.p. washing with pirarubicin cured 2-day-old, but not 7-day-old, peritoneal carcinomatosis in rats. Short exposure to i.p. pirarubicin is nontoxic and more active than povidone-iodine and other anticancer drugs in preventing the development of peritoneal carcinomatosis from colonic origin in rats and mice. The prophylactic effect of preoperative peritoneal washing with pirarubicin on the development of recurrent peritoneal cancer should be evaluated in a randomized clinical trial.

Topics: Animals; Anti-Infective Agents, Local; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Colonic Neoplasms; Doxorubicin; Immunosuppressive Agents; Injections, Intraperitoneal; Male; Mice; Mice, Nude; Neoplasm Seeding; Peritoneal Lavage; Peritoneal Neoplasms; Pharmaceutical Solutions; Povidone-Iodine; Rats

Though the first choice of treatment for liver metastasis in colon cancer is surgical resection of liver, 30-60% of such patients experience a recurrence of liver metastasis. Even if reoperation is done optimally, the surgical resection of liver metastasis may not be a definitely curative treatment. For cases of liver metastasis from colon cancer that are non-resectable due to multiple liver metastases, other organ metastases (lung, bone, brain etc.), the advanced age of the patient, or other complications (cerebrovascular disease, diabetes mellitus, heart disease etc.), hepatic arterial infusion or systemic combination chemotherapies are selected. In the present paper, we report 3 cases of effective systemic chemotherapy utilizing CPT-11 for liver metastases from colon cancers. The method was UFT + irinotecan (CPT-11), cisplatin (CDDP) + tegafur + CPT-11, UFT + CPT-11 + etoposide (ETP) + pirarubicin (THP). The result obtained was a partial response (PR) in each case. As there were few adverse effects, we could provide treatment during a short-term admission or an outpatient basis. We thus obtained good post-chemotherapeutic QOL, and these regimens may be effective forms of chemotherapies in the future.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Etoposide; Female; Humans; Irinotecan; Liver Neoplasms; Male; Tegafur; Uracil

This study was performed to evaluate the antimetastatic activity of antitumor agents against metastatic colon carcinoma 26 (Co 26Lu), and to investigate their mechanisms of action. Pirarubicin demonstrated the most striking antitumor activity in mice bearing intravenously injected Co 26Lu cells. Etoposide and mitoxantrone also showed marked antitumor activity. Pirarubicin and mitoxantrone also exerted remarkable inhibitory effect on spontaneous lung metastases from subcutaneously implanted Co 26Lu. Pirarubicin showed marked inhibition of both primary tumor growth and lung metastases. Mitoxantrone was effective in preventing lung metastases even at doses that did not exhibit an antitumor effect on the primary tumor. Moreover, mitoxantrone administered two days after intravenous injection of tumor cells obviously reduced the number of lung colonies, while simultaneous injection of the drug did not inhibit colony formation. Mitoxantrone effectively inhibited angiogenesis on the chorioallantoic membrane at doses that did not affect the growth rate of embryos. These results suggest that mitoxantrone, besides its direct antitumor effect on tumor cells, may inhibit lung metastases by inhibiting angiogenesis.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Cell Division; Colonic Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; Endothelium, Vascular; Etoposide; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mitoxantrone; Neoplasm Transplantation; Neovascularization, Pathologic; Rats

Pirarubicin (THP) is a derivative of adriamycin (ADM) which has been reported to have a lower cardiotoxicity than ADM. The authors investigated the in vivo antitumor effect of THP against human colon cancer cells (RPMI 4788) xenografted into nude mice. In the model of intra-abdominal carcinomatosis, intraperitoneal administration of THP (6 mg/kg) resulted in a significant prolongation of the survival compared with the saline control group (p less than 0.01). Intravenous administration of THP (8 mg/kg) significantly inhibited tumor growth compared with the saline control group. Labeling index with bromodeoxyuridine (BrdU) of RPMI 4788 tumors treated with THP was smaller than that in the control group. Mitotic index was also smaller in the group treated with THP. Labeling index with BrdU indicates the proportion of cells in the S phase. Thus, the tumor cells in both S and M phases have decreased after treatment with THP. This change in the cell cycle progression may be due to the accumulation of G2 phase similar to in vitro study. From these results, it was suggested that the change in cell cycle progression revealed in vitro might be caused by THP in vivo.

Topics: Animals; Antibiotics, Antineoplastic; Cell Cycle; Colonic Neoplasms; Doxorubicin; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Tumor Cells, Cultured

The cytotoxic activities of several natural and semisynthetic anthracyclines against L1210 leukemia and two human colon tumor cells (Colon 4, HT 29) in vitro were examined after short (1 h) and long (7 days) incubation times and correlated with the water/octanol partition coefficients and the DNA-binding affinity of the compounds. Analysis of equation in which cytotoxicity against L1210 (1-h incubation) was parabolically related to the partition coefficient revealed an almost exclusive correlation (r = 0.80) between the cytotoxicity and the parameters, and this correlation was only slightly improved by addition of DNA-binding affinity (r = 0.85). On the other hand, cytotoxic activities displayed after continuous incubation were partially related to both partition coefficients (parabolic dependence) and DNA-binding affinities (linear dependence). In this case the correlation between the activity and partition coefficient (r = 0.67) was significantly improved by addition of DNA-binding affinity (r = 0.90). Similar results were also obtained for human colon tumor cells although the corresponding correlation coefficients were generally of lower value, indicating that cytotoxic activity of anthracyclines against these primary resistant cells may be influenced by additional factors not yet determined.

Topics: Animals; Antibiotics, Antineoplastic; Chemical Phenomena; Chemistry, Physical; Colonic Neoplasms; DNA; Humans; Leukemia L1210; Molecular Structure; Neoplasms; Regression Analysis; Structure-Activity Relationship; Tumor Cells, Cultured

A phase II study on THP((2''R)-4'-0-Tetrahydropyranyladriamycin) was performed in 47 patients with advanced or recurrent gastrointestinal cancer through the cooperation of nine institutions in Hiroshima Prefecture from April 1982 to November 1984. THP was given by means of intravenous infusion and/or intraaortic infusion and the 47 cases were divided into two groups according to the method of administration: (A) 40-60 mg/body every 3 or 4 weeks, or (B) 30 mg/body every week. Among 24 evaluable cases, partial response (PR) was observed in two cases of recurrent metastatic lymph nodes in gastric cancer patients. The (A) method of administration was more effective than (B). Subjective side effects observed were appetite loss, nausea, vomiting and general fatigue, but these were not so severe. Leukocyte nadir occurred at the 1st or 2nd week of THP administration, but thrombocytes were not appreciably decreased.

Topics: Antineoplastic Agents; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Liver Neoplasms; Rectal Neoplasms; Stomach Neoplasms

A phase II study of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP) was performed on 37 patients with gastrointestinal cancer in 6 co-operative study institutions. Twenty-five patients out of 37 were evaluable for response according to the Koyama-Saito's criteria. THP was administered weekly at doses of 10 to 30 mg/body or every 3 to 4 weeks at doses of 40 to 60 mg/body intravenously. Of the 14 patients with gastric cancer, we obtained one complete response and 3 partial responses (response rate 28.6%), and of the 6 patients with rectal cancer, we obtained one partial response (16.7%). Leukopenia of less than 3 X 10(3)/mm3 and erythrocytopenia of less than 300 X 10(4)/mm3 were seen in 48% and 26% of cases. Neither cardiotoxicity nor hair loss were seen. These results suggest that THP is useful in the treatment of patients with gastrointestinal cancer.

Topics: Adult; Anorexia; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukopenia; Male; Middle Aged; Nausea; Rectal Neoplasms; Stomach Neoplasms

Chemotherapy with 4'-O-tetrahydropyranyladriamycin (THP-ADM), a new derivative of Adriamycin, was equally or more effective against several experimental mouse tumors than it was with Adriamycin (ADM). When mice with P388 leukemia were given i.p. injections of THP-ADM or ADM daily for 9 consecutive days, the maximum increases in life span (ILSs) of the mice were 190 and 175%, respectively. Eight of 24 mice treated with THP-ADM were free of tumor, while one of 24 mice treated with ADM was free of tumor. A single i.p. injection of either drug was also effective; maximum ILS was 170% for mice treated with THP-ADM and 240% for those treated with ADM. Nine of 12 mice were found to be free of tumor. THP-ADM was equally or slightly more effective against P388 leukemia than was ADM when either drug was given i.v. The maximum ILS was 106% with THP-ADM and 77% with ADM when the drug was given for 9 consecutive days. Single i.v. injections of THP-ADM or ADM were almost equally (ILS, 100%) effective. Chemotherapy with THP-ADM was also very effective against L1210 leukemia. THP-ADM administered i.p. five times, every other day starting from Day 1, was more effective than ADM was against Lewis lung carcinoma, B16 melanoma, and colon adenocarcinoma 38 inoculated s.c. In the study with Lewis lung carcinoma, metastasis to the lungs was well suppressed by THP-ADM. ADM was more effective than was THP-ADM against colon adenocarcinoma 26. Because THP-ADM was more cytotoxic than or almost equally as cytotoxic as ADM against the established cell lines from the above mouse tumors, we suggest that THP-ADM is more efficiently transported into cultured cells.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line; Colonic Neoplasms; Doxorubicin; Leukemia P388; Lung Neoplasms; Melanoma; Mice; Mice, Inbred Strains; Neoplasms, Experimental