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.

There have been many attempts to treat patients with malignant brain tumors represented by glioblastomas using nitrosourea (NU) derivatives such as BCNU and CCNU but the clinical results are not so remarkable compared with previous reports concerning experimental studies. The reason for an efficacy of NU derivatives in brain tumors is considered to be its higher lipid solubility which makes the drug crossing the BBB easily. On the other hand, there is some evidence that higher lipid solubility did not guarantee NU to reach always to all portions of solid tumor after systemic administration. We have performed a chemotherapy of malignant brain tumors using ACNU for five years. This drug is not only lipid but also water-soluble in some grade; therefore, the drug is administrated intravascularly and locally with ease. Nine cases of malignant gliomas were treated with local chemotherapy employing ACNU and two cases of glioblastomas are surviving now over five years and about four years, respectively. From the anatomical standpoint of view, it is considered to be necessary for local chemotherapy of brain tumors to possess some pathognomonic characters such as cyst formations, central necrosis and localized cortico-meningeal adhesions, which are rather frequently found in malignant gliomas and are suspected also easily by CT examination preoperatively. A local chemotherapy in the present study has been performed using 10 to 50 mg of ACNU through an indwelling catheter inserted during operation. No general toxicity occurred in all patients except one, who experienced purulent meningitis after long-term drainage. In our study on concentration of ACNU, intracarotid injection resulted in higher concentration in brain tumor tissue than intravenous injection, but these concentration considered to be not high enough to suppress the tumor cell growth. On the other hand, the intracavitary concentration of ACNU at 24 hr after drug administration was high enough to suppress the tumor cell growth.

A new fluoropyrimidine antitumor agent, carmofur (HCFU, Mifurol) was administered to patients with malignant ovarian tumor. Two of these patients revealed favorable results. The first patient was a 72-year-old female, who was diagnosed as having ovarian serous cystadenocarcinoma with metastatic omental tumor at exploratory laparotomy, its size was newborn child head size. She was started on with a combination chemotherapy of Mifurol (600 mg p.o. daily), Endoxan (4 mg/kg i.v. twice a week), Mitomycin C (0.04 mg/kg i.v. twice a week) and Toyomycin (0.01 mg/kg i.v. twice a week). After four weeks, this combination therapy brought her a complete response with disappearance of pleural effusion, ascites and metastatic tumor. The second case was a 39-year-old female, who underwent adnexectomy elsewhere which led to the discovery of Krukenberg tumor, and was referred to our hospital. After the first course of the same combination chemotherapy, second look operation was performed. Histological examination of the specimen obtained by metastatic tumor of uterosacral ligament showed the degeneration (grade II b-III, Oboshi and Shimozato) of cancer cell. It is suggested that this combination chemotherapy including Mifurol is effective and useful for the patients with ovarian carcinoma.

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.

Levels of futraful (FT-207), 5-FU and Uracil in blood and tissue were measured on 11 cases of oral malignant tumors after administration of UFT. 1) After administration of UFT, the highest level of 5-FU was detected in tumor tissue followed by the normal lymph node, metastatic lymph node, and normal tissue which showed the lowest level. 2) Levels of 5-FU in serum was lower than in tumor, and T/S ratio of levels of 5-FU was 9,190. 3) There were significant regressions in levels of 5-FU and Uracil in normal lymph node (p less than 0.02). Coefficient of correlation was 0.469. 4) Comparisons of levels of 5-FU after administration of UFT and futraful were 1.89 in tumor, 1.72 in normal tissue, 1.80 in metastatic lymph node and 1.55 in normal lymph node. Level of 5-FU after administration of UFT was higher than that of futraful. 5) Higher level of 5-FU after administration of UFT in tumor tissue and lymph node were maintained for a longer period.

The present study was designed to evaluate the efficacy of chemotherapy by NCS for advanced and/or recurrent carcinoma of the pancreas, mainly nonresectable cases in which exploratory laparotomy or construction of biliary fistula were performed. Three hundred fifty seven cases were available for the study. Of the 357 cases, 116 were treated with NCS alone 5-FU. In the former, the efficacy rate was higher in cases with 2,000 mu/body of NCS every day than in those with 4,000 mu/body of NCS intermittently 2-3 times for a week. 19.6% of the cases treated with more than 40,000 mu of NCS alone in total were interpreted as effective clinically by Karnofsky's criteria of I-A over. In the latter, the efficacy rate was higher in cases with 2,000 mu/body of NCS combined with 250 mg of 5-FU every day than in those with 4,000 mu of NCS combined with 500 mg of 5-FU intermittently, 22.5% of the cases given more than 40,000 mu of NCS in total were interpreted as effective clinically by Karnofsky's criteria of I-A over. The major adverse effects of NCS such as anorexia, vomiting and nausea were observed in 20% of total cases respectively, leucopenia in 10% and fever in 15% of them.

This study was designed to evaluate the most effective administration method of NCS for advanced carcinoma of the stomach, mainly nonresectable and/or recurrent cases which were collected by our cooperative study group. Nine hundred seventy six cases were available for clinical evaluation. Rate of the efficacy of NCS alone and combined with 5-FU was higher (P less than 0.1) in the cases administrated intravenously by drip infusion than in those by one shot injection method, and adverse effects were fewer in the former than in the latter cases. The rate of efficacy of NCS was higher in cases treated with 4,000 mu/day alone intermittently 2-3 times for a week than in those with 2,000 mu/day alone every day. The rate of clinical effect was higher in the cases treated with 4,000 mu of NCS combined with 50 mg of 5-FU intermittently than in those with 2,000 mu of NCS combined with 250 mg of 5-FU every day, especially 20.6% of the former cases given more than 50,000 mu of NCS were interpreted as clinically effective by Karnofsky's criteria of I-A over.

Effects of BAI with PEP 30 mg+MMC 10 mg on 26 patients with lung cancer were evaluated in comparison with 34 cases treated with single PEP or MMC. Histopathological findings of the cases treated with PEP+MMC and PEP alone showed more effective results than that of MMC alone. The tumor decreased rate on the chest X-ray film of the cases treated with PEP+MMC was highest and the cavity formation was also typical in the cases with PEP+MMC and PEP alone. The side effects of the cases with PEP+MMC were able to reduce markedly to about 50% compared with single administration of PEP or MMC; however pulmonary fibrosis and necrotizing bronchitis were noted in 8%.

Using C3H/He mice a series of experiments was carried to study the antitumor effect of lipopolysaccharide (LPS) in combined use with Lentinan extracted from Cortinellus shiitake and its influence on cellular immunity as well as antitumor effect of tumor necrosis factor (TNF) prepared from LPS, and the following results were obtained: 1) In the cases where LPS was administered when the tumor had grown to a certain extent after tumor transplantation, hemorrhagic necrosis of the tumor occurred within 48 hours, showing a high antitumor effect. 2) In the cases where LPS was used with Lentinan, i.e., 2 mg/kg/day of Lentinan was administered from the 1st to the 8th day after tumor transplantation, and 30 micrograms/kg of LPS given on the 12th day, the highest antitumor effect could be achieved. 3) By combined use of LPS and Lentinan delayed type hypersensitivity was intensified. 4) Upon application of rabbit serum containing TNF to cancer bearing mice, hemorrhagic necrosis of the tumor was observed within 48 hours, and a superior antitumor effect compared to LPS alone was noted in terms of tumor size and weight.