As a preliminary study to apply thermotherapy or thermochemotherapy to the treatment of peritoneal dissemination of gastric cancer, a continuous hyperthermic peritoneal perfusion (CHPP) was carried out for the experimental peritoneal dissemination of Donryu rats inoculated with AH100B ascitic hepatoma cells (AH100B cells). Firstly, the cytotoxicity of heat on AH100B cells was studied. No cytotoxicity was observed at 37 degrees C, but mild cytotoxicity was noted at 41.5 degrees C, and marked rise in cytotoxicity was seen at 42.5 degrees C. These cytotoxicity increased with addition to Mitomycin C and prolongation of the heating time. Next, on the 1st, 5th and 10th day after inoculation of AH100B cells, the Donryu rats were treated as follows: Group 1; CHPP (37 degrees C for 1 hr), Group 2; CHPP (41.5 degrees C for 1 hr), Group 3; (42.5 degrees C for 1 hr), Group 4; CHPP (41.5 degrees C for 1 hr)+MMC 1 mg/kg (intraperitoneal administration immediately after completion of CHPP). Group 5; MMC 1 mg/kg (intraperitoneal administration). Death within 48 hours after perfusion occurred in one rat of the 41.5 degrees C perfusion group and 14 rats of the 42.5 degrees C perfusion group. Comparison of the survival time on these groups showed the most remarkable life-prolonging effect in CHPP (41.5 degrees C)+MMC group. On the basis of the results of this study, the CHPP method combined with anti-cancer chemotherapy is considered to be an useful treatment for peritoneal dissemination of cancer.

The mechanisms of action of, and resistance to, important anticancer agents are briefly described. Their selective toxicity is considerably high, and is chiefly due to the distribution and metabolism in the body. The selective toxicity of some DNA-binding drugs may be attributed to the structural difference of DNA, nucleosome and/or chromatin between neoplastic and normal cells. Some studies of reducing side effects are summarized. In our laboratory, we are studying drug-resistance and metastasis of tumor cells. Since the mechanism of natural resistance of gastric cancer, pulmonary cancer, and other refractory cancers may be related to acquired resistance of leukemia, studies on new agents against drug-resistant tumor cells are important. In our laboratory, we have selected cell sublines of murine T-lymphoblastoma L5178Y for resistance to adriamycin (ADM), aclarubicin (ACR) or bleomycin (BLM), and have observed that the resistance is attributed to decreased influx and increased efflux of the antibiotic, resulting in lowered retention of the drug in the cells. Each resistant subline shows a characteristic cross-resistant pattern, suggesting that membrane alteration involved differs each other. We have also found that glycoprotein-synthesizing activity and alkaline phosphodiesterase activity of plasma membrane are higher in the three resistant sublines than in the parental cell line. We obtained a number of hybridomas producing antibodies to plasma membrane of an ACR-resistant subline of L5178Y cells. Among the syngeneic monoclonal antibodies, one was found by agglutination tests to react with the ACR-resistant cell line, but not significantly with the parental and ADM-, BLM-and MCR-resistant cell lines. Fluorographs of [14C] leucine-labeled ACR-resistant cells demonstrates two protein bands of 230 K and 20 K daltons, which are precipitated by the monoclonal antibody. The former seems to be specific to the ACR-resistant cells. Based on the results so far obtained, the 230 K protein may be related to the drug resistance and may be TATA (tumor-associated transplantation antigen). The results suggest that isolation of drug-resistant neoplastic cells is a novel method of finding TATA.

The human tumor colony-forming assay was used to compare chemosensitivity among tumor cells within a primary tumor, between primary tumor and its metastasis, and between different metastases. The results indicate that the reported discrepancies of in vitro and in vivo results in clinical trials with TCFA for predicting of resistance or sensitivity to cytostatic drugs may be due to therapeutic heterogeneity among tumor colony-forming units within a primary tumors and between primary tumor and metastases, and that the results from a metastatic lesion may have more profound implications in planning treatment of other metastatic lesions of the same patient.

Cytotoxic and cytokinetic effects of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl) 3-nitrosourea hydrochloride (ACNU) on cultured rat and human glioma cells (C-6 and KC) were studied in vitro. Exponentially growing culture cells were exposed to ACNU at the final concentrations of 5 micrograms/ml, 20 micrograms/ml, and 80 micrograms/ml, respectively. The cytotoxic effect was evaluated by inhibition of cell growth and the cytokinetic effect was analyzed by DNA histogram using a flow cytometer. Inhibition of cell growth was dose-dependent in ACNU and C-6 cells were more resistant than KC cells. The growth of C-6 and KC cells were not inhibited at all by low concentrations of ACNU (5 micrograms/ml, 20 micrograms/ml), however, at these concentrations a marked accumulation of treated cells in S and G2+ M phases was evident. The accumulation in S and G2+M phases was dose-dependent and it was more prominent in KC than C-6 cells. ACNU-treated cells accumulated initially in S phase and then in G2+M phase. After maximum accumulation in G2+M phase, the cells seemed to be released into G1 or G0 phase. These results indicate that the cytokinetic effect of ACNU (5 micrograms/ml, 20 micrograms/ml) is more conspicuous than the cytotoxic effect on C-6 and KC cells.

Effects of a water-soluble nitrosourea derivative, 1-(4-amino-2-methylpyrimidin-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride [ACNU]. on survival and cell progression of HaLe S3 cells was investigated. The survival of exponentially growing cells exposed to increasing concentrations of the drug was characterized by a threshold-type survival curve (D0 = 7.0 micrograms/ml X 1 hr, Dq = 3.5 micrograms/ml X 1 hr). ACNU exerted its main killing effect on cells in G1 and G2 + M phases, whereas cells in S phase were resistant to the drug. Changes in survival response as a function of cell cycle were mainly dependent upon the extent of the exponential slope of the survival curve. Cell progression effects were examined by using a low concentration of ACNU in which 80% of treated cells could survive. Cells in G1 and early S phases at the time of treatment were not prevented from entering S phase but prolonged in duration of S phase followed by a marked delay in progression through G2 phase. However, such a delay in cell progression time was reduced in cells treated in mid S phase as compared with G1 and early S phases. Cells treated in late S and G2 phases could normally progress into mitosis.

A phase II study of vindesine was performed by National Chest Hospital Lung Cancer Cooperative Study Group involving 21 institutions. Of 91 patients who entered into the study, 68 patients were evaluable. Response rates were 11.8% (3/33), 8.3% (1/12) and 14.3% (1/7) for small cell, adeno, squamous cell, and large cell carcinoma of the lung, respectively. Vindesine was given by bolus i.v. injection at doses of 3 to 5 mg weekly, and the total doses ranged from 12 to 24 mg with 8 responders. Adverse reactions of vindesine were leukopenia (less than 3000 cells/cmm, 54%), anorexia, peripheral neuropathies, hairloss, etc., but they were generally reversible and the discontinuation of treatment was rare.

A total of 48 patients with various malignant disorders, mostly from hemopoietic organs, entered to phase I study of MCNU given orally. Fifty-six percent of the patients given MCNU at the doses of 50-125 mg/m2 complained of gastrointestinal symptoms including nausea and vomiting, which were however mild and well tolerated. In the following study employing administration of 50 mg/day of MCNU for consecutive 2-6 days, the gastrointestinal toxicities were reduced to 26.1%, and hematological toxicities of delayed leukopenia and thrombocytopenia were derived 4-6 weeks after oral intake of the drug. The hematological recovery required 1-2 weeks after the nadir of leukocyte and thrombocyte count. A recommended dose for phase II study of MCNU by the route of oral administration was 50 mg/body/day for consecutive 4-6 days in every 8 weeks interval. The peak value of blood concentration of MCNU was obtained 60-120 minutes after p.o. administration at the doses of 50-100 mg. Elimination half-life was estimated to be 40-45 minutes. No concentration of the drug was detected in blood 24 hours after the administration.

4'-Epiadriamycin demonstrated considerable efficacies in lymphomas, breast cancer and soft part sarcomas with reduced gastrointestinal, hematologic and probably cardiac toxicities. Mitoxantrone appears to be established the clinical role in lymphomas, acute leukemia and breast cancer with mild clinical toxicities. A new analogous compound of cisplatinum CBDCA concluded phase I study and the dose limiting factor was thrombocytopenia. It is of interest that the drug had responders in ovarian cancer during phase I study. The results reported in new anthracyclines; marcellomycin, carminomycin and 4-demethoxydaunorubicin, anthraquinones; ametantrone and bisantrene, new cisplatinums; CHIP, DACCP and TNO-6, and various other drugs including mAMSA, 5'-DFUR, spirogermanium, VP-16-213 and AZQ were reviewed.

Twenty liver cancer patients, including 9 hepatocellular carcinoma and 11 with metastatic liver cancer, were treated by intra-arteral one-shot chemotherapy. Alterations in blood coagulation and fibrinolysis were observed serially after one-shot chemotherapy by testing the levels of PT, APTT, FDP, fibrinogen, AT III, alpha 2-macroglobulin, and plasminogen. APTT was prolonged, FDP increased, Fbg increased after a transicent decrease, and AT III, alpha 2-M, and plasminogen decreased. The peaks of these alterations occurred within 7 days after the one-shot treatment; recovery was observed after about weeks. The more advanced the cancer, the greater were the alterations.

The nitrosourea compounds are often used in the treatment of patients with malignant brain tumors in combination with anticonvulsants, such as phenobarbital (PB). Since PB can induce hepatic microsomal enzyme--P 450 and degrade nitrosoureas in vivo, the effect of PB on tumoricidal activity in relation to toxicity of 3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) was studied using a rat brain tumor model. To determine toxicity, CD-Fisher rats were treated for 4 days with 19 and 38 mg/kg/day of PB (i.m), 0.4 and 0.7 g/kg/day of sodium valproate--SV (p.o), or 3 days with 50 mg/kg of phenytoin (i.v) prior to an administration of 47 mg/kg of ACNU (i.p). The mortality rate by the toxicity within 14 days after administration of ACNU was calculated in each group. The toxicity of ACNU was markedly reduced in PB pretreated rats compared with those without pretreatment or treated with SV or phenytoin. The tumoricidal activity of ACNU was evaluated in CD-Fisher rats with RG 12 brain tumors. Rats received 20 mg/kg ACNU after pretreatment with 19 mg/kg/day of PB (i.m) or 0.2 g/kg/day of SV (p.o) for 4 days. The mean survival days and the percentage increase in life span (%ILS) were compared in each group. Pretreatment with PB significantly reduced the tumoricidal activity of ACNU as compared with control without pretreatment (p less than 0.001) or pretreatment with SV (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)