The anti-emetic effect, safety and clinical usefulness of ondansetron for the treatment of nausea and vomiting caused by anticancer drugs including cisplatin, was evaluated by a multi-institutional study in patients with various malignancies. In this study, ondansetron was given intravenously with mainly a single dose of 4 mg to intervene nausea and vomiting. 1. Efficacy ratio of overall effects on nausea and emesis observed for 24 hours after treatment was 69.8%. 2. No side effect was observed. Laboratory tests showed temporary elevation of serum uric acid level in 1 patient in the group given 4 mg. 3. From these results, it seems that ondansetron, given intravenously after initial vomiting, was highly safe and clinically useful anti-emetic for the treatment of nausea and vomiting associated with anti-cancer drugs.

We examined the anti-emetic effect, safety and usefulness of ondansetron hydrochloride, a selective 5-HT3 receptor antagonist, given orally once daily at the dosage of 4 mg, for 3 to 5 consecutive days to patients with nausea and emesis induced by non-platinum anti-cancer drugs such as cyclophosphamide, doxorubicin and carboplatin. Out of 84 cases where anti-emetic effects were evaluated, numbers of cases assessed as excellent and good were 36 (83.3%) and 34 (40.5%), respectively, the efficacy rate being 83.3% (70/84). Side effects, such as moderate constipation (3 cases) and mild headache (3 cases), were observed in 8/85 cases (9.4%). Abnormalities in clinical laboratory findings including elevation of hepatic function and uricacid values and increase in eosinocyte counts, were observed in 3/85 cases (3.5%). As to overall safety, 78/85 cases (91.8%) were evaluated as having no problem in safety, and 7/85 cases (8.2%), as having minor problem in safety. As to clinical usefulness based on anti-emetic effect and overall safety, out of 79 cases the drug was assessed as very useful in 29 cases (36.7%) and useful in 35 cases (44.3%), the rate of "useful" or above being 81.0% (64/79). Furthermore, when ondansetron was administered in 3 courses of chemotherapy, though the number of patients was small, it was shown that anti-emetic effect of ondansetron did not decline and no problem in safety was observed. From the above, ondansetron which exerted adequate anti-emetic effect in 4 mg once daily doses was considered as a useful and safe anti-emetic in treatment of nausea and emesis associated with cancer chemotherapy.

Menogaril (TUT-7) is a novel antitumor antibiotic belonging to anthracyclines. The pharmacokinetic parameters derived from plasma concentration-time profiles after repeated (for 14 days) or single oral administration of TUT-7 to rats were found to be not significantly different by either administration schedule. The rats with artificial liver dysfunction were obtained by subcutaneous application of carbon tetrachloride (CCl4, 1 ml/kg) for 3 days. After oral administration of TUT-7 to the rats with CCl4-induced liver toxicity (3 daily administrations of 1mg/kg, S.C.), the maximum plasma concentrations (Cmax) and AUC of both the unchanged drug and its metabolite N-Demethyl menogaril, were increased. Also over all elimination was slower in animals with liver dysfunction.

Ototoxicity of cis-diammine glycolato platinum, 254-S, was evaluated from the results obtained in phase II studies for head & neck cancer, lung cancer, breast cancer, gastrointestinal cancer, urogenital cancer and gynecological cancer at 114 institutions, and in randomized comparative study of 254-S plus vindesine vs. cisplatin plus vindesine for advanced non-small cell lung cancer conducted at 41 institutions. In these studies, 254-S was administered at doses ranging from 80 to 100 mg/m2, repeated at least 2 times at 4-week intervals. Impaired hearing was examined in a hearing audiometry test before and after 254-S administration. The incidence of impaired hearing was 25.8% (16/62) in the 254-S phase II studies. The incidences in the randomized comparative study were 17.6% (3/17) for the 254-S/vindesine group and 20.0% (3/15) for the cisplatin/vindesine group. From these results, the ototoxicity of 254-S was thought to be similar to that of cisplatin in incidence and type.

A phase III study of DWA2114R for ovarian cancer was carried out in CAP regimen by a cooperative study group consisting of 42 institutions. The response rate of 31 cases for DWA2114R regimen was 38.7% and out of 30 cases for CDDP regimen 46.7%. No significant differences were observed between the two regimens in efficacy, adverse reactions, and abnormalities in laboratory findings except for red blood cell and creatinine clearance, but the incidence of thrombocytopenia was likely to be lower in DWA2114R than in CDDP regimen. Since the DWA2114R regimen did not need hydration, or require diuretics, DWA2114R is more useful in the treatment of ovarian cancer than cisplatin.

DWA2114R (DWA) is a new derivative of platin compounds. Eleven patients with rapidly progressive, endocrine-resistant stage D carcinoma of the prostate were treated with infusion of DWA (800-1,000 mg/m2) every 3 to 4 weeks. A partial objective response was observed in 3 of 11 patients (27%). This response lasted from 5 to 11 months with an average of 7.7 months. Six patients (55%) had a significant decrease or disappearance of bone pain and five became ambulatory and asymptomatic. Four patients (36%) showed no change, and four patients (36%) did not respond to the treatment and showed progression of their disease. There were no patients with severe leukopenia (less than 1,000/mm3). No significant renal toxicity was observed in any of the patients and gastrointestinal toxicity was tolerable. DWA appears to be an effective drug available for the treatment of endocrine-resistant advanced carcinoma of the prostate.

A phase II clinical study of 254-S, a new anticancer platinum complex for advanced breast cancer, was conducted by the 254-S Breast Cancer Study Group consisting of 6 institutions nation-wide. Considering the results of the phase I clinical study, 254-S was administered at 100 mg/m2 by intravenous drip infusion and this administration was repeated at least 2 times at 4-week intervals. Of 19 patients registered, 16 were evaluable for tumor response (complete cases). Partial response (PR) was obtained in 2 patients, for a 12.5% response rate. Major toxic effects observed were hematotoxicity thrombocytopenia and leukopenia, and gastrointestinal toxicity (nausea and vomiting, and anorexia), though there was no case in which the treatment with 254-S had to be discontinued due to the toxic effect.

A multi-institutional phase II study of DWA2114R was conducted in breast cancer. DWA2114R at doses of 800-1,000 mg/m2 was administered by 1-hour intravenous infusion every 3-4 weeks on minimal two cycles. Fifty-two patients entered the study; 34 were eligible, 7 ineligible. Eleven patients were dropped from evaluation due to incomplete observations. There were 1CR, 6PR, 1MR, 12 NC, and 14 PD with an overall response rate of 20.6%. A median duration of responses was 11 weeks. Leukopenia and nausea/vomiting were frequently observed but well tolerated and recovery was quick. It is concluded that DWA2114R is a useful drug in the treatment of breast cancer.

A phase I study on a weekly schedule of DWA 2114R, a new platinum analogue, was conducted in 21 patients with various tumor types by clinical groups at 10 institutions. Nineteen of the 21 patients entered in this study were evaluable. The starting dose was 200 mg/m2 (1 n) administered intravenously for 1 hr and gradually escalated stepwise to 700 mg/m2 (3.5 n). The dose limiting factor (DLF) was leukocytopenia, especially neutropenia and maximum tolerated dose (MTD) was 700 mg/m2. The major clinical toxicity was gastrointestinal. Nephrotoxicity and hepatotoxicity were mild. Ototoxicity and cardiac failure did not emerge. Following administration of the drug, total platinum (Pt) showed a biphasic decay and AUC of total Pt was dependent on the dose. Excretion into urine 24 hr was between 42.6 and 100% of the administered platinum. The recommended dose of phase II study on a weekly schedule was 600 mg/m2, repeated every 2 or 3 weeks and administered via intravenous within drip infusion.

The antitumor activity of kefir (YK-1), a fermented milk product in Caucasus, was investigated. YK-1 at oral doses of 100 or 500 mg/kg inhibited the proliferation of solid tumor of Ehrlich ascites carcinoma transplanted subcutaneously in mice. YK-1 did not show an inhibitory effect on the ear swelling induced contact dermatitis caused by picryl chloride (PC-CD). However, YK-1 inhibited the immunosuppression in Ehrlich carcinoma-bearing mice and with the frozen and dried ascites of the tumor-bearing mice containing immunosuppressive substances (EC-sup) in PC-CD-induced mice. And also, YK-1 activated the immunosuppressive activity of spleen cells of mouse treated with EC-sup. These results suggest that YK-1 may have antitumor activity against Ehrlich carcinoma and activate the immunosuppression with it.

A phase II study of 5'-deoxy-5-fluorouridine (5'-DFUR) tablets for breast cancer was done at 31 institutions in Japan. Forty-five patients were registered and 44 of them were eligible for the study. Of the 40 patients whose results could be evaluated, 11 (28%) responded (four complete responses and seven partial responses). Side effects, such as diarrhea, anorexia, leukocytopenia, and liver dysfunction were observed in 24 of the 44 patients. The side effects were mild and transient. 5'-DFUR is a promising drug for breast cancer treatment, and its tablet form makes chemotherapy easier for the patient.

A phase II clinical study of 254-S, a new anticancer platinum complex, for cervical cancer was conducted by the 254-S Cervical Cancer Study Group consisting of 10 institutions. 254-S was administered at 80 mg/m2 by intravenous drip infusion and this administration was repeated at least 2 times at 4-week intervals, in principle. Forty of 45 patients registered, were eligible and 38 were evaluable for tumor response (complete cases). Complete response (CR) and partial response (PR) were obtained in 4 (10.5%) and 9 patients (23.7%), respectively, for a 34.2% response rate. Against squamous cell carcinoma, a 38.2% response rate (4 CR and 9 PR in 34 patients) was obtained. The response rate obtained in patients with no prior chemotherapy was 40.0% (2 CR and 8 PR in 25 patients), while that in patients with prior chemotherapy was 23.1% (2 CR and 1 PR in 13 patients). Major toxic effects observed were hematotoxicity, including thrombocytopenia (35.1%), leukopenia (73.0%), anemia (75.7%), gastrointestinal toxicity such as nausea and vomiting (83.8%) and anorexia (83.8%). Nephrotoxicity observed was in the form of an elevation of serum creatinine with an incidence of 2.7% and a decrease in creatinine clearance with an incidence of 21.7%. In comparison with the results obtained in the phase II clinical study for gynecological cancers in which 254-S was administered at 100 mg/m2, the response rate obtained in this study was slightly lower but thrombocytopenia and leukopenia observed were less frequent and milder. Based on these results, it was concluded that 254-S is a very useful anticancer agent for the treatment of cervical cancer.

An early phase II clinical study of 254-S, a new anticancer platinum complex, for head and neck cancer was conducted by the 254-S Head and Neck Cancer Study Group consisting of 10 institutions. Based on the results obtained in the phase I study, 254-S was administered at 100 mg/m2 by 60 min intravenous drip infusion after being dissolved in 300 ml of 5% xylitol. In principle, the 254-S administration was repeated at least 2 times at 4 week intervals. Hydration was performed, if needed. All 24 cases registered were regarded as complete cases evaluable for tumor response. Complete response (CR) was observed in 4 patients (16.7%), partial response (PR) in 5 (20.8%), no change (NC) in 11 and progressive disease (PD) in 4, for a 37.5% response rate. Three CR and 3 PR (40.0%) were obtained in 15 patients with prior chemotherapy, including 1 CR and 2 PR (33.3%) in 9 patients previously treated with cisplatin. Side effects were observed in 19 patients (79.2%). Major toxic effects were hematotoxicity, including thrombocytopenia (58.3%), leukopenia (58.3%) and anemia (33.3%), and gastrointestinal toxicity, including nausea and vomiting (45.8%) and anorexia (37.5%). Abnormal parameter changes on renal function were found in 2 patients (8.3%). Based on these results, it was concluded that 254-S is potentially a useful anticancer agent for the treatment of head and neck cancer, and should be further investigated in a late phase II clinical study.

A new platinum complex 254-S had a superior preclinical therapeutic indices compared to cisplatin, showing decreased renal and gastrointestinal toxicities. Phase I clinical study with a single dose schedule was conducted to investigate the safety, toxicity, pharmacokinetics and possible efficacy against various advanced cancers by a cooperative study of 10 institutions. The drug was administered by i.v. infusion for 60 min dissolved in 250 ml of 5% xylitol solution, without the use of hydration and antiemetics. At least 3 patients at each dose level of 10, 20, 40, 80, 100 and 120 mg/m2 were tested and 28 patients were entered into this study. Myelosuppression, especially thrombocytopenia, appeared strongly at dose level of 80 mg/m2 and dose limiting thrombocytopenia was found in 2 of 5 patients. Leukocytopenia was also dose-related but moderate. Platelet and WBC nadirs occurred around 3 weeks after administration with recovery in about one week. Although slight elevation of BUN and creatinine were temporarily observed in a few cases, no significant renal toxicity was observed. Anorexia, nausea and vomiting were observed in the majority of patients, but milder than cisplatin. In conclusion, 254-S has demonstrated reduced non-hematologic toxicities as compared to cisplatin. This drug appears to be well tolerated and 120 mg/m2 was maximum tolerated dose. The recommended dose for phase II studies was thought to be 100 mg/m2 by i.v. infusion every 4 weeks.

Since the prognosis of patients with malignant ascites is generally poor, the establishment of a therapeutic plan should be done as soon as possible. In order to select the most suitable antitumor agent, a drug-sensitivity test was done by MTT assay using fresh autologous tumor cells as targets. Autologous tumor cells were collected from their ascitic fluids. Results obtained here indicate a possible strategy for the treatment of patients with malignant ascites by MTT assay.

Effects of anthracycline type antitumor agents (aclarubicin, ACL; daunorubicin, DAU; doxorubicin, DOX; epirubicin, EPI; pirarubicin, PIR) on the acute toxicity to mouse, rat liver microsomal lipid peroxidation and mitochondrial functions in vitro were studied. ACL showed the least production of liver microsomal lipid peroxidation in all tested anthracyclines in the increasing order of PIR, DOX, DAU and EPI. The increase of production of lipid peroxidation induced by these drugs correlated well with the decrease in body weight of mice administered i.p. at 20 mg/kg and 50% lethal dose of these drugs. On the effect of mitochondrial function, all drugs tested decreased the oxygen uptake of state 3 and the level of respiratory control index. ACL showed the most severe inhibition of these functions in all drugs. These observations suggest that the degree of microsomal lipid peroxidation induced with the anthracycline drugs was related to the development of the drug acute toxicity.

A phase II clinical study of 254-S, a new anticancer platinum complex, for primary lung cancer was conducted by the 254-S Lung Cancer Study Group consisting of 15 institutions nation-wide. Considering the results of the phase I clinical study, 254-S was administered at 100 mg/m2 by intravenous drip infusion and this administration was repeated at least 2 times at 4-week intervals. Of 75 patients registered, 61 patients consisting of 22 with small cell lung cancer (SCLC) and 39 with non-small cell lung cancer (NSCLC) were evaluable for complete tumor response. Partial response (PR) was obtained in 17 patients, for a 27.9% response rate. The response rate for SCLC was 40.9% (9 PR in 22 patients) and that for NSCLC was 20.5% (8 PR in 39 patients). In SCLC patients with no prior chemotherapy, a 50.0% (5 PR in 10 patients) response rate was obtained. In those with prior chemotherapy, the response rate was 33.3% (4 PR in 12 patients). In NSCLC patients with no prior chemotherapy, a 22.6% (7 PR in 31 patients) response rate was obtained. In hose with prior chemotherapy, the response rate was 12.5% (1 PR in 8 patients). Major toxic effects observed were hematotoxicity such as thrombocytopenia and leukopenia, and gastrointestinal toxicity such as nausea, vomiting and anorexia. Nephrotoxicity observed was mild and infrequent in spite of the low-volume hydration performed. Based on these results, it was concluded that 254-S is a useful anticancer agent for the treatment of primary lung cancer.