A phase II clinical trial of an anthraquinone, mitoxantrone was performed in a total of 31 patients with various advanced solid tumors and 2 patients with malignant lymphomas refractory to extensive prior chemotherapies. Mitoxantrone was administered at dosages of 2 to 4 mg/m2 with a 5-day schedule or 6 to 12 mg/m2 with a one day schedule, repeating at 4-week intervals. Of 18 evaluable patients with breast cancer, one out of 2 patients who had not been exposed to regimens containing adriamycin achieved partial response lasting 3.6 months, while the remaining 16 patients exposed to adriamycin did not respond. Leukopenia less than 4 X 10(3)/cm3 and thrombocytopenia less than 100 X 10(3)/cm3 were observed in 100% and 55% of cases, respectively. Nausea and vomiting were observed in 36% of cases. Diarrhea, pyrexia, liver damage, mucositis and palpitation were observed in one case each. No ECG abnormality was recorded.

Since interferon (IFN) has a mechanism of action very different from chemotherapeutic agents, it is possible that a combination of two may be of therapeutic value. The authors studied increased cytotoxic effects of anticancer drugs by IFN on human tumors xenografts in nude mice. Tumor used in this study were "SH-10", "S-7379" (gastric cancer) and "O-7294" (malignant melanoma), serially transplanted subcutaneously. IFN was injected, 5 X 10(5) mu/mouse, every day for 2 weeks and a single drug was administered 3 times every fourth day. Cytotoxic effect was determined by tumor size on day 16 after treatment. Of the 7 drugs, MMC and ADM were most effective. Other drugs showed a slight inhibition of tumor growth by combination therapy with drugs and IFN.

Two kinds of, serially transplantable human tumor cell lines were established in nude mice in ascitic form. One is breast cancer cell line, poorly differentiated adenocarcinoma, Hattori strain, and the other is acute lymphocytic leukemia cell line, T-cell type, Ichikawa strain. There exists a distinct correlation between the survival time of nude mice and the number of tumor cells transplanted. Clinically established antitumor agents which showed over 200% increase in life span were MMC, ADM and 5FU in Hattori strain, and VCR, VLB, VDS, ADM and BH-AC in Ichikawa strain. These results were considered to be consistent with the clinical effect of these drugs in breast cancer or in acute lymphocytic leukemia. Both strains can serve as the reliable screening system of antitumor agents.

Sixteen of 20 patients(80%) with adult ANLL treated with B H-AC X AMP therapy attained complete remission (CR). According to the FAB classification, CR rate was 6 out of 8 (75%) for M1, 3 out of 5 (60%) for M2, 2 out of 2 (100%) for M3, and 5 out of 5 (100%) for M4. The median of remission duration in 16 patients who attained CR was 8 months and appeared to be longer in patients with M2, rather than other types, of leukemia than in those with the other types of leukemia. BH-AC X AMP therapy is highly effective for remission induction in adult ANLL and long term disease free survival could be expected by addition of appropriate maintenance therapy.

A 67-year-old patient with stage C giant prostate cancer was treated with a combination of endocrine administration and chemotherapy. After administration of diethylstilbestrol diphosphate (250 mg/D, 16 days), bilateral orchiectomy and subsequent CDDP administration (30 mg/D X 5 days, e. 3 weeks, 4 courses), the primary tumor was reduced by about 90%. Clinical response was evaluated as partial response. Serum acid phosphatase activity, prostatic acid phosphatase, prostate antigen and nuclear DNA histogram served as useful tumor markers and changed in parallel to clinical course.

The method of the human tumor clonogenic assay and its clinical correlations have been reported here. True positive rate for predicting of sensitivity to cytostatic drugs has been characteristically low. Results of our studies indicate that discrepancy of in vitro and in vivo results in clinical trials with the tumor clonogenic assay may be due to therapeutic heterogeneity among tumor colony-forming units within a primary tumor and between primary tumor and metastases.

In forty-eight samples from ovarian cancer patients, in vitro colony assay was carried out. The success rate of growing tumor colonies was 63% and the plating efficiencies was 0.06%. The in vitro sensitivity to standard drugs for the treatment of ovarian cancer was seemed to be compatible to that in clinical use. The predictive accuracy for sensitivity of this assay was 20% and 73% for resistance. Ovarian cancer cells can be formed colonies well and this assay method can be used for evaluation of various anticancer drugs in vitro.

Accurate in vitro anticancer drug sensitivity is helpful for successful chemotherapy of cancer patients. The purpose of the present study was to evaluate the tumor stem cell assay for the selection of effective drugs for individual patients with cancer and for the in vitro phase II screening of new anticancer drugs. Sixty-six specimens obtained from cancer patients were tested drug sensitivity by this assay. The results showed that this assay as an excellent technique for testing in vitro sensitivity of anticancer drugs against tumor cells from specimens removed from individual patients. The in vitro results correlated with in vivo response data in 93% of the instances observed in vitro-in vivo associations and a true negative rate was 100%.

An in vitro drug sensitivity test was developed to estimate the lethal effects of drugs on cancer cells. Cancer cells we incubated in the presence of radioactive precursors and anticancer drugs. The drug effects were estimated from the changes in rates of incorporation of precursors into DNA, RNA, and protein. Handling of a large number of samples became possible using a microtiter plate and a multiple automatic cell harvester. Incorporation of radioactive precursor showed linear correlation with drug-induced lethality. The results of this test were also correlated well with in vivo regression of tumors of mice. This test appeared to be more reliable than other similar test of cell lethality in vitro. For utilization in clinical studies, a test plate was simplified and 25 human cancers were tested. The results demonstrated the generally good correlation between in vitro and in vivo tumor sensitivities.

In vitro chemosensitivity test of human solid cancers, serially transplanted into nude mice was performed by detecting the inhibitory rate of 3H-thymidine incorporation to cancer cells. And the results of in vitro chemosensitivity test were compared with those in nude mice. This in vitro chemosensitivity test could present the quantitative results from a relatively small number of cancer cells within a short term (48 hours). Additionally, many samples could be handled at the same time by using microtestplates and a semiautomatic multiple cell harvester. The predictability of this in vitro chemosensitivity test to the in vivo effects was 80.6% (29/36) with 3 false positive and 4 false negative cases.

In order to improve the response rate of chemotherapy, we have investigated to the method for rapid and accurate prediction of the most appropriate anticancer agents. Thus, a rapid method using nude mice has been established as in vivo model for assessing chemosensitivity of individual human tumors, in which the final evaluation was made with 3H-thymidine incorporation and histological changes of tumor cells treated. Correlation between the sensitivity of anticancer agents and retrospective results of gastrectomy in stage IV gastric cancer was investigated. Our sensitivity test indicated a good correlation with clinical therapeutic and immunological effects. From these results, it seems reasonable to conclude that the sensitivity test using human tumor/nude mouse system may be useful for selection of appropriate agents to treat patients with cancer.

Experimental studies with orally administered MCNU, a water-soluble nitrosourea, yielded the following results. MCNU produced a significant increase in life span, and 60-day survivors were observed by various schedules in L1210 leukemia. The therapeutic ratios of MCNU were almost similar to those of CCNU. With Lewis lung carcinoma and Ehrlich ascites carcinoma implanted into the stomach wall, its antitumor activity by oral administration was slightly more effective than by intravenous route. In Beagle dogs, hematologic toxicity and gastrointestinal toxicity (vomiting, diarrhea) were noted by oral administration, similar to intravenous administration, but its toxicity was mild. The maximum blood level of MCNU was noted at 30 minutes after oral administration in Beagle dogs. The half life (23.7 min) by oral administration was similar to that by intravenous route. From these results, the oral administration of MCNU deserves the consideration as a form of treatment now given other MCNU routes.

Pneumonitis-fibrosis which was induced by the treatment with antineoplastic agent(s) and/or irradiation was encountered in 37 (14.1%) of a total of 515 patients with lung cancer who had been treated in our institute during a period of seven years from 1976 through 1982. Of 251 patients who had been treated with bleomycin or pepleomycin alone or in combination with other antineoplastic agent(s) or irradiation, 46 (18.3%) had pneumonitis-fibrosis and 19 (7.6%) died therefrom. It was revealed that the patients over 50 years of age, whose PaO2 and % VC prior to the treatment with bleomycin were less than 79 mmHg and 79% respectively appeared to be predisposed to bleomycin pulmonary toxicity. Most of the pneumonitis which developed in these patients was progressive and fatal. Daily oral administration of 10 mg of prednisolone was in effective for the prevention of bleomycin-induced pneumonitis-fibrosis. A sudden decrease of PaO2 and a sharp elevation at a certain point in time during treatment were indicative of the fatal outcome of toxic pulmonary complications. Thoracic irradiation prior to, concomitant with or after bleomycin therapy enhanced the pulmonary toxicity of bleomycin. Therefore, combination therapy should be avoided. A continuous intravenous infusion may be the most effective and least toxic method to administer bleomycin.

Combined treatment with intraarterial administration of oily anti-cancer agent (SMANCS-Lipiodol; copolymer of styrene maleic acid conjugate of Neocarcinostatin disolved in Ethiodol) and transcatheter arterial embolization (TAE) was employed in 2 patients with small hepatoma. At 3-4 weeks after treatment, hepatic resection was performed. Histopathological examination of the 2 resected specimens showed total cell necrosis; CT and Softex revealed the distribution of lipiodol in the tumor and adjacent regions. This combination treatment showed combined effects, i.e. embolization by TAE, the anti-cancer effect of SMANCS and the selective delivery of lipidol to the hepatoma, especially the area of capsula invasion, the daughter nodule and tumor thrombus.

Fourteen cases of adenocarcinoma with pleuritis carcinomatosa (lung cancer 10 cases, ovarian cancer 2 cases, colon cancer 2 cases) were treated with intra-pleural instillation of 7-N-(p-hydroxyphenyl)-mitomycin C (KW-2083), a derivative of mitomycin C. KW-2083 was administered at a dose of 40 mg once or twice weekly. In 14 evaluable patients, the rate of decrease of pleural fluid was 79%, and that of disappearance of tumor cells in pleural fluid was 64%. Median survival time (MST) from the beginning of treatment in all cases was 163 days. The toxicities of intrapleural instillation of KW-2083 were chest pain (86%), transient fever (64%), anorexia (64%), fatigability (29%), nausea (21%), vomiting (21%) and thrombocytopenia (nadir: 3.5 X 10(4)/mm3; 7%). Serum and pleural fluid KW-2083 concentrations have been measured in 3 patients after intrapleural administration of KW-2083. The mean half life of KW-2083 in serum and pleural fluid was 74 min (69-78 min) and 56 min (33-70 min), respectively. The peak serum KW-2083 concentration was 0.18 microgram/ml (0.06-0.24 microgram/ml).