A pharmacokinetics and platinum concentration in the gynecologic organs were measured following the intravenous drip infusion of 375 mg/m2 of CBDCA. Total platinum (TP) in plasma decreased biphasically and free platinum (FP) was almost monophasically eliminated. The t 1/2 of FP was about 51 min. and the percentage of FP out of TP at four hours after administration was more than 92%, which was much higher proportion compared with that of cisplatin (CDDP). A cumulative excretion of platinum in the urine within 24 hours was 69%. The platinum concentration in the benign part of portio and endocervix were higher than that of malignant portion, although there were no significant differences in other pelvic organs such as ovary and tubes. However, pelvic lymph-nodes showed less platinum concentration both in metastatic and non-metastatic tissues. Platinum concentration in the tissue did not change significantly with lapse of time. Bone marrow suppression was observed especially in the patients who had received chemotherapy or radiotherapy. No renal toxicity was observed even without any hydration and gastro-intestinal toxicity was much milder than that of CDDP.

After a hysterectomy, a bilateral salpingo-oophorectomy, two courses of intra-peritoneal chemotherapy of Cisplatinum, Carmofur (HCFU, 600 mg/day [per os]) were given a patient who had ovarian granulosa cell tumor (malignant, stage Iai). Dizziness and loss of consciousness developed about 60 days after administration of HCFU, and leucoencephalopathy was diagnosed. A CT revealed a diffuse low density area in the white matter of the cerebrum. Myelin Basic Protein in the spinal fluid was found to amount to 9.8 mg/dl, which in norm. person is less than 4.0 mg/dl. Also, it showed parallel changes with the course of the clinical findings. HCFU easily dissolves to fat and changes to 5-FU without enzymes in the liver cell. Further HCFU also passes through Blood Brain Barrier to Produce 5-FU and its derivatives, in which the alpha-Fluoro-beta-Alanine is thought to be the culprit that brings on leucoencephalopathy. Even so, HCFU should be dosed when needed in spite of this risk. Other 5-FU modifiers also have been reported to produce the same effect in several cases.

SM-5887, a new totally synthetic anthracycline derivative, was studied in a phase I setting. Twenty-nine evaluable courses of treatment were conducted in groups at doses increasing from 10 to 130 mg/m2. At 130 mg/m2 the median lowest WBC count was 0.7 x 10(3)/mm3 (range 0.3-1.8) and the median lowest platelet count was 57 x 10(3)/mm3 (range 4-176). Nonhematological side effects were mild gastrointestinal symptoms and hair loss. The recommended dose and schedule for a phase II setting is 100 mg/m2 every 3 weeks.

The effect of antitumor agents on the cell cycle traverse of cultured FL cells, a monolayer culture line derived from human amnion, was investigated by flow cytometry (FCM) in combination with simultaneous determination of total cell number, viability, mitotic index and labeling index by [3H]TdR. The results obtained can be summarized as follows: Antimetabolites prolonged the duration of the S phase at a low dose, while at a high dose they decreased the rate of progression from the G1 to S phase, resulting in G1 and G1-S boundary accumulation. Partial synchronization by these agents was obtained through two different mechanisms. In vinca alkaloid-accumulated cells in the G2+M phase at 24h, mitotic index (MI) reached 20%, which was 10 to 20 times higher than that of control and most M-phase cells, which consisted of metaphase cells. Other cells in a tetraploid state were considered to be in the G2 phase or possibly G1 phase of the tetraploid cycle. Antibiotics generally accumulated cells in the G2 phase, but agents could be divided into two groups according to the degree of G2 accumulation. One group showed almost complete G2 accumulation, while the other showed only partial accumulation. The former group inhibited the progression of the S phase at a higher dose. Both groups completely inhibited the progression of the cell cycle at the highest dose. Alkylating agents only partially accumulated cells in the G2 phase at a low dose, showed prolongation of the S phase at a high dose, and inhibited the progression of the cell cycle at the highest dose, as with antibiotics. On the basis of these results, the application of these agents for treatment of cancer, especially leukemia, is discussed from a rational viewpoint.

A phase II clinical trial on MDS was conducted in a cooperative study with orally administrable ara-C analogue, PLAC, which is resistant to cytidine deaminase and had shown an anti-tumor activity on various experimental tumors by oral route. Fifty MDS (3 RA, 18 RAEB, 11 RAEB-T, 18 RAEB-blast crisis (BC) were treated orally with 100 to 400mg/body of daily PLAC. One good response (GR) and 3 partial responses (PR) were obtained in 18 RAEB, and 2 complete remissions, 1 GR and 1 PR were noted in 11 RAEB-T, while 3 PR were seen in 18 RAEB-BC. Overall CR rates were 4%, GR rates 4% and PR rates 14%. Thus, 22% of MDS responded to oral PLAC. No clear daily dose-response was noted. Response, however, was dependent on the treatment period and was obtained in cases which had been treated for more than 20 days. Besides myelosuppression, side effects were mainly gastrointestinal, and anorexia (32%), nausea/vomiting (30%) and diarrhea (8%) were observed. Oral PLAC seems to be active on MDS which does not necessarily require admission to hospital.

A 76-year-old man with lung carcinoma, who was undergoing both radiotherapy and chemotherapy (CDDP + ADR) suddenly died with the onset of abdominal symptoms. Autopsy disclosed that the main cause of death was suppurative panperitonitis, caused by a perforation of a metastatic lesion at the jejunum. A histological examination revealed extensive tumor necrosis in the metastatic liver lesions as well as in the jejunal lesions. Neither inflammatory nor circulatory damage was observed in the perforated lesion. Therefore, the cause of this perforation was considered to be chemotherapy that had brought on tumor necrosis. No similar reports of lung cancer deaths have been found in the literature in which the microscopic details were described. Accordingly, this case is reported for future reference with regard to cancer chemotherapy.

The mechanism of action of anti-cancer drugs, especially 5-FU, was discussed on the basis of RNA metabolism. After its incorporation into cells, 5-FU is metabolized through the uracil pathway, and finally incorporated into various species of RNA. On the other hand, 5-FU metabolized to FdUMP forms a covalent ternary complex among TS and mTHF, and inhibits de novo TMP synthesis, resulting in the inhibition of DNA synthesis. However, 5-FU was found to exert an effect on TS- mutant FM3A cells which was almost as lethal as the effect on wild-type FM3A cells in the presence of thymidine. Therefore, this lethal effect could be attributable to the inhibition of RNA metabolism, rather than DNA metabolism. The effects of 5-FU on RNA metabolism in L1210 cells are as follows: (1) inhibition of the processing of preribosomal RNA to ribosomal RNA (2) inhibition of the synthesis of poly(A) RNA of mRNA (3) inhibition of tRNA methylation (4) impaired synthesis of snRNA, U4, U6. (5) inhibition of pre-rRNA methylation (6) enhancement of poly(A) RNA translation. With reference to the items listed above, a discussion was made on the basis of our experimental results.