Sixty-seven patients with hematological malignancies and 4 with cancers were evaluated in this study. Standard administration of MCNU was instituted intravenously using 50-100 mg/m2 every 2 or 4 weeks, whereas some cases were treated with a higher dose therapy. Of 10 patients with chronic myelogenous leukemia, 7 achieved complete remission (CR), and 1 achieved partial remission (PR). A good response was also obtained in 9 of 10 patients with polycythemia vera and in all 4 patients with essential thrombocythemia. MCNU was less effective in malignant lymphoma (ML) and multiple myeloma (MM) than in myeloproliferative disorders. Two of 15 patients with ML and one of 21 patients with MM achieved CR, and two with ML and three MM achieved PR. Three patients with lung cancer and 1 with gastric cancer showed no response to MCNU. Delayed anemia, leukocytopenia and thrombocytopenia were observed in 38.7% of patients, and these were regarded as major side effects of MCNU. Nausea, vomiting, anorexia and elevated transaminase were also found in about 24% of patients, but only transiently. Our study indicates that MCNU is useful for chemotherapy of hematological malignancies, especially of myeloproliferative disorders. Therefore, further studies on combination chemotherapy with MCNU should be developed.

We tried an in vitro sensitivity test for the purpose of examining the effect of anti-neoplastic agents and their enhancement by Biscolaurine Alkaloid (Cepharanthin). Methods, HeLa cells were synchronized by excess of thymidine and hydroxyurea, and resuspended in Eagle's MEM with 10% FCS. The cells were mixed with Mitomycin C or Bleomycin and added to the wells of a microtiter plate. When required, Cepharanthin (the effect of this drug is considered to change the plasma membrane liquidity) was added to the medium, and then cultured for 24 hours in a CO2 incubator. After culture, each well received 3H-thymidine, and was incubated for 8 hours. The cells were harvested for the assay of 3H-thymidine.

Ketoconazole (Nizoral), an orally active antimycotic agent with a broad spectrum, has been reported to interfere with steroidogenesis both in patient and in vivo rat studies. It has also been shown that the same drug inhibits some P-450--catalyzed reactions in adrenal cortex mitochondria. In the present work, we studied the inhibitory effect of Ketoconazole, along with some other known inhibitors of steroidogenesis, on the reconstituted steroid monooxygenase system, which consists of adrenodoxin, its reductase and P-450 11 beta as the protein components being purified from bovine adrenal cortex mitochondria. The results indicated that; Ketoconazole completely inhibited hydroxylation of deoxycorticosterone at the 11 beta-position to form corticosterone and at the 18-position to form 18-hydroxydeoxycorticosterone. The Ki value for Ketoconazole, calculated either from the 11 beta-hydroxylase reaction or the 18-hydroxylase reaction, was 0.56 microM, which was comparable to the value obtained for metyrapone in the same system. Ketoconazole also inhibited 18-hydroxylation of corticosterone to form 18-hydroxycorticosterone, with 50% inhibitory concentration of less than 0.03 microgram/ml. The corresponding value for this inhibitor in the deoxycorticosterone 18-hydroxylase reaction was found to be 0.3 microgram/ml. The contrast between these values for the two substrates is striking. Thus, in a series of reaction steps, the inhibitory effect of corticosterone to 18-hydroxycorticosterone was more potent than deoxycorticosterone to 18-hydroxycorticosterone reaction. Both trilostane and o, p'-DDD over the wide concentration range failed to inhibit any of the reconstituted P-450 11 beta system similar to those applied to the Ketoconazole study.(ABSTRACT TRUNCATED AT 250 WORDS)

A phase II study of VP-16, a semisynthetic Podophyllotoxin, was performed in patients with solid tumors. VP-16 was administered orally at a dose of 200mg/day for 5 consecutive days at 3 to 4-week intervals. Out of 41 patients who were entered into the study, 35 patients comprising 17 lung cancer, 10 hepatoma and 8 other tumors were evaluable. There were 4 partial responses (23.5%) for lung cancer, 1 (10.0%) for hepatoma and 1 for rhabdomyosarcoma. Overall response rate was 18.2% for patients with prior chemotherapy and 15.4% for those given no prior chemotherapy respectively. Thus the results indicated VP-16 has no cross-resistance to other antitumor agents. Leukopenia (less than 4,000/mm3) and thrombocytopenia (less than 10 X 10(4)/mm3) were observed in 72.7% and 29.4% of the patients, respectively. Other toxicities were alopecia (59.5%) and gastrointestinal disturbances such as nausea (46.2%), vomiting (20.5%) and anorexia (20.5%), but these were all well tolerated.

In this paper, we demonstrated a selection system of anti-cancer agents (ACA) using discontinuous Ficoll density gradient method (DFDGM) for purification of tumor cells and 3H-Thymidine for evaluation of DNA synthesis of tumor cells. The tumor cells, purified to more than 80% by DFDGM, were contacted with ACAs for 3 days from the culture initiation and tumor suppression rate (TSR) by ACAs were calculated by following formula; TSR = ACA(-)cpm-ACA(+)cpm-background cpm divided by ACA(-)cpm-background cpm X 100% 7 ACAs; Mitomycin C (MMC), Adriamycin (ADM), 5-Fluorouracil (5-FU), Cytosine Arabinoside (Ara-C), Carbazilquinone (CQ), ACNU and Cis-platinum (CDDP) were examined in 106 cancers; 60 breast cancers, 18 gastric cancers, 23 colorectal cancers and 5 others. ADM and CQ showed high TSR against breast cancers, CQ against gastric cancers, and 5-FU and CQ against colorectal cancers, respectively. The reliability of this ACA selection system should be evaluated by future clinical studies, however, we stress that ACA should be selected by not only the effect on tumor cells but also the effect on immunity of the host, in future.

To evaluate the effect of anticancer chemotherapeutic antigens on rat prostate, ten kinds of anticancer agents corresponding to the dose generally used for humans were intraperitoneally injected to 63-day-old Wistar rats. The anticancer agents were administered as follows: Cyclophosphamide (CPM) was used at the dose of 8 mg/kg for 7 days. Methotrexate (MTX), actinomycin-D (ACD) and cis-platinum (CDDP), 163 micrograms/kg, 8 micrograms/kg and 833 micrograms/kg for 5 days, respectively. Nitrogen mustard (NM), bleomycin (BLM), peplomycin (PLM), adriamycin (ADM), vincristine (VCR), and vinblastine (VBL), 500 micrograms/kg, 250 micrograms/kg, 170 micrograms/kg, 2.5 mg/kg, 33 micrograms/kg and 83 micrograms/kg, twice in a week, respectively. The rats were killed on the fifth day after completion of the schedule. Then, the weight of the body, the prostate, the epididymis and the adrenal gland were measured. In addition, 5 alpha-reductase activities and histological findings in the prostate were examined. For determination of 5 alpha-reductase activities, cell-free homogenate obtained from the rat ventral prostate was incubated with C14-testosterone at 37 degrees C for 30 minutes in an atmosphere of 95% of O2 and 5% of CO2. Subsequently, the metabolites from testosterone were separated and purified with thin layer chromatography using the solvent system with benzene acetone, 4:1 (v/v). 5 alpha-Reductase activity was determined with the sum of dihydrotestosterone (DHT) and androstanediol converted from testosterone and indicated as pmol product/mg protein. The 5 alpha-reductase activity was employed as a biological marker for the degree of androgenic dependency in the prostate. The results were summarized as follows. CDDP significantly reduced the weight of the body (p less than 0.001, n = 7), but not the activity of 5 alpha-reductase. NM and VBL had a specific action to reduce the weight of the prostate (p less than 0.01, n = 8) without causing loss of body weight. NM and VBL showed no influence on 5 alpha-reductase activities. The activity of 5 alpha-reductase was markedly damaged by BLM (p less than 0.05, n = 6) and PLM (p less than 0.05, n = 5). However no significant reduction was recognized in the weight of the body and the prostate. CPM, MTX, ACD, ADM and VCR were ineffectual on the body and the prostate weight and 5 alpha-reductase activities. In the histological examination, atrophy and degeneration of the glandular epithelium were revealed in the prostate treated with NM, VBL and CDDP.(ABSTRACT TRUNCATED AT 400 WORDS)

We examined the effects of domperidone suppository against adverse reactions in digestive organs to antitumor agents. Suppositories containing 60 mg of domperidone were given to 15 patients who were suffering from vomiting and nausea occurring with the use of antitumor agents, and the changes in each digestive symptom were evaluated overall. As a result, 13 patients out of 15 (86.7%) showed improvement of symptoms. There were no adverse reactions to domperidone suppositories.

Studies of anthracycline antibiotics which have been carried out for the purpose of finding compounds useful in the treatment of cancer are described. Synthetic development of derivatives and analogs which have stronger activities and lower characteristic toxicities than parent antitumor antibiotics such as daunomycin, adriamycin, etc., have been illustrated namely: (1) syntheses of 4'-O-derivatives such as 4'-O-tetrahydropyranyl-adriamycin; (2) syntheses of N-alkyl derivatives such as 3'-deamino-3'-morpholino-adriamycin; and (3) syntheses of 11-deoxy-adriamycin. Notably, 4'-O-tetrahydropyranyl-adriamycin having a (2" R)-configuration has been confirmed to have stronger activity and lower toxicity than adriamycin by Phase II study. New, naturally occurring anthracycline antibiotics (decilorubicin, arugomycin, ditrisarubicin, etc.) have also been reviewed.

Using our new in vitro antitumor sensitivity assay, the basis of which depends on predictive analysis of morphological findings of L1210 leukemia cells under the influence of antitumor agents, 5 kinds of nitrosoureas including MCNU were comparatively tested for antitumor activity. A cell killing effect became apparent very soon under BCNU and CCNU, rather late under Methyl-CCNU and MCNU, and intermediately under ACNU. Various cellular biological effects were apparently induced in L1210 cells by MCNU and its mechanism of action seemed to be broader than that of any other members of the nitrosoureas.

Immunomodulatory and antitumor activities of the low molecular weight, microbially-derived immunomodulators, bestatin and forphenicinol are reviewed. In addition, the inhibitory effects of the antitumor antibiotics, aclacinomycin and oxanosine, on the generation of suppressor cells are also represented. It is suggested that these substances will be useful for cancer treatment by chemotherapy and/or immunotherapy.

Spergualin, named after the spermidine and guanidine moieties in its structure, was isolated from culture broth Bacillus laterosporus of based on its greater growth-inhibitory activity against chick embryo fibroblasts (CEF) transformed by Rous sarcoma virus compared with that against normal CEF. The structure of spergualin was determined as (-)-(15S)-1-amino-19-guanidino-11, 15-dihydroxy-4, 9, 12-triazanonadecane-10, 13-dione. Spergualin is water-soluble, basic and a white powder. It shows cytotoxicity in vitro against mouse leukemias L1210 and L5178Y. It significantly prolongs the life span of mice transplanted with either of the above leukemic cells. It induces a strong and specific immunological effect on L1210 which has been maintained in our laboratory; L1210-transplanted CDF1 mice, once cured by spergualin, reject a second challenge of the leukemic cells. Spergualin hibits in growth in vitro of both Gram (+) and (-) bacteria at concentrations ranging from 6.25 to 100 micrograms/ml.