Transcatheter arterial chemoinfusion and/or chemoembolization of the internal iliac artery have been used for the treatment of pelvic malignancies. Intraarterial chemoinfusion is expected to deliver a higher concentration of chemotherapeutic agents directly to the neoplasm, reducing the problems of systemic side effects. In 35 cases of pelvic malignancies, 61 procedures of intraarterial chemoinfusion and/or chemoembolization of cisplatin (CDDP) and/or adriamycin (ADR) were performed in combination with or without occlusion of the superior and/or inferior gluteal arteries by the use of steel coils. For chemoinfusion and chemoembolization, the anterior division of the internal iliac artery was selected. In 19 procedures of 14 cases, pain of the lower extremities and the hips developed soon after chemoinfusion and chemoembolization, and gradually followed by paresthesia. Each patient was complicated with numbness, dysesthesia and/or weariness of the lower extremities, thighs and the plantar and dorsal of the foot. These symptoms continued long without recovery. Additionally, the most severe complication such as paralysis and muscular atrophy of the unilateral lower limb occurred in one patient, and at the 14 months follow-up the patient was still suffering from paralysis and gait disturbance. A neurologic examination revealed damage of the sciatic nerve at the level of L5, S1 and S2. It was suggested that the cause of the neurologic complications was attributed to ischemia and/or to deliver a higher concentration of chemotherapeutic agents of the sciatic nerves, and that any previous surgery, radiotherapy or intraarterial chemoinfusion combined with embolization was not related to the symptoms under discussion.

Subrenal capsule assay as a chemosensitivity test was performed on 8 renal cell carcinomas and 7 transitional cell carcinomas using athymic mice. Twelve of the 15 trials were considered suitable for evaluable assay. In 2 of the 3 non-evaluable trials the histological examination showed fibroblasts without cancer cells in the implants of the control group while the implants grew macroscopically. No host cell infiltration was observed microscopically in any implant of the control groups of evaluable assays. Mice were treated with several anticancer agents and sensitivities were evaluated by the tumor growth inhibition rate (TGIR) on the day 10 or 12 and by histological changes. No correspondence was observed between TGIR and histological changes. The characteristic histological finding of the treated groups of transitional cell carcinomas was cystic degeneration and it seemed to be a factor of the discordance between TGIR and the histological changes.

The ovarian toxicity induced with 12 oncostatics was evaluated using syngeneic mice, 6-week-old C57BL/6. Each drug diluted with saline to 0.2ml was intraperitoneally infused twice at 6 and 7 weeks old. Mice were sacrificed 2 weeks after the second treatment, the ovaries removed and fixed for serial sectioning, and the small oocytes of Pedersen and Peters counted. Small oocytes were destroyed in a dose-dependent fashion, and ED50, an effective dose of which produced 50% destruction of small oocytes in each mice group, was significantly divided into 4 groups of statistical difference (F = 5.77, p less than 0.0213). The smallest dose of ED50 (mg/mouse) (the strongest in oocyte toxicity): Actinomycin D 0.0064, doxorubicin 0.0184, peplomycin 0.021; the second: Bleomycin 0.107, mitomycin 0.0707, CDDP 0.120; the third: Cyclophosphamide 0.427; and the largest (the weakest): Ifosphamide 3.01, 5FU 6.17, etoposide 6.11, methotrexate 2.0 much less than, vinblastine 0.1 much less than. The most toxic included those which could attack not only DNA, but also RNA biosynthesis and the least included those which could have an effect on enzymes or proteins with no direct action on DNA. The ratio of ED50 to HUD, the single usual dose for human cancer chemotherapy, were smallest for doxorubicin (2.23), cyclophosphamide (2.59) and CDDP (5.19). Although these three are very useful oncostatics for ovarian cancer, they might have serious potential toxicity for human ovarian oocytes.

Forty-four patients with progressive symptomatic multiple myeloma were treated with a protocol combining cyclophosphamide (10 mg/kg weekly), procarbazine (2 mg/kg daily), prednisolone (20 mg daily), and either BCNU (1 mg/kg weekly) (BCPP protocol) or MCNU (0.8-1 mg/kg) (MCPP protocol). Of these, 34 patients were treated with the former, and 10 patients with the latter. With BCPP protocol, 12 achieved a complete response, 11 evidenced a 75% response, and 7 displayed a 50% response. With MCPP protocol, on the other hand 2 achieved a complete response, 6 showed a 75% response, and 1 exhibited a 50% response. The median tumor halving time in both groups was 77 days and 57 days respectively. The 5-yr disease-free survival of patients treated with BCPP protocol was 62.0 +/- 10.8%. In MCPP group, 8 of 10 patients are alive with more than 49-87 weeks survival. Although myelotoxicity was moderate, other toxicities were moderate. Toxicity requiring dose modification and discontinuation of the scheduled therapy was observed.

Temporary blockage of uterine and ovarian vessels with forceps led to an approximately two-fold increase in the transfer of LMOX and Carboplatin to uterine muscle, ovarian tissue and pelvic lymph-nodes after the release of forceps. This result suggests the importance of preserving these main vessels for the effective transfer of chemotherapeutic agents to target tissues. Ten cases in stage III or IV underwent cytoreductive surgery followed by three courses of CDDP, ADM, CPA chemotherapy and SLO (postop. group). A further 27 cases were given diagnostic laparotomy followed by the same chemotherapy and SLO (preop. group). Examination of both groups revealed the following: The efficacy rate of the CAP regimen was 77.8% in the preop. group and 50.0% in the postop. group; the surgical extirpation rate exceeding 90% at SLO was 76.1% and 50.0% in the preop. and postop. groups respectively. The survival period was longer in the preop. group, ie., two years in 69% versus 40% and three years 43% v 20% of the preop. and postop. groups, respectively. Preoperative (Neo-adjuvant) chemotherapy followed by aggressive surgery was concluded to be preferable to carrying out enforced reduction surgery first on such advanced cases where the mass of the residual disease cannot be left untouched is unavoidable.

The anticancer activity of KW2149, a new derivative of mitomycin C (MMC), was investigated against 5 human tumor xenografts derived from digestive organs using 4-day subrenal capsule assay (SRCA). Normal immunocompetent mice were used in this assay. For the comparative study, KW 2149 and MMC were administered intraperitoneally for 3 days after implantation, and the anticancer activity and the weight loss of mice were evaluated. The total doses were determined as 1/2, 1/3 and 1/4 of LD50 value of each anticancer agent. The anticancer activities of the two drugs were almost the same with no significant difference in 3 xenografts. Thus, it may be suggested the difference of the anticancer spectrum between the two drugs. The anticancer activity of KW2149 indicated higher correlation with the administered doses as compared with MMC. The toxicity of KW2149 was almost the same as MMC according to the weight loss of mice.

Because of technical difficulties, the pharmacokinetics of neocarzinostatin (NCS) have not been thoroughly evaluated in patients with malignant glioma. The authors produced anti-NCS antibody by immunizing rabbits with NCS and established a means of quantifying tissue levels of NCS with enzyme-linked immunosorbent assay. In one patient given a bolus injection of 1 mg of NCS intra-arterially, the concentration of drug in neoplastic tissue at 25 minutes (0.1136 micrograms/g) was higher than that in blood at 20 minutes and was retained for a longer period. Rapid entry of NCS into the tumor cavity was observed at 5 minutes. In two postoperative cases, NCS applied topically to the tumor site (50 and 100 micrograms) was retained at high levels (0.2941 and 3.33 micrograms/ml) even after 48 hours, although no NCS was detected in blood after 60 minutes. NCS concentrations as low as 1 microgram/ml demonstrated cytocidal effects, and a delay in tumor growth was observed even at an NCS level of 0.1 microgram/ml, despite the fact that the half-life of NCS is extremely short (3 seconds in serum). Because its cytotoxic effect seems to be very rapid, it appears more important to obtain a high initial NCS concentration than to maintain a constant blood level.

Experiments have been carried out to determine the effect on the cell survivals at different time intervals between irradiation and chemotherapeutic agents (BLM, cisDDP, ADM and ACNU) in either the in vivo or the in vitro system. The intestinal epithelial assay was applied on the in vivo system. The clonogenic cell survivals of V79 cells, both in the proliferative and the plateau phases, were determined in the in vitro system. The V79 cells in the plateau phase were more sensitive to BLM, cisDDP and ACNU than those in the proliferative phase, however, the result was reverse with ADM. When BLM, cisDDP or ACNU was combined with irradiation at different time intervals, the response of the plateau phase V79 cells to combination therapies were very similar to those of the intestinal epithelial cells. On the other hand, V79 cells in the proliferative phase, which were treated with ADM and irradiation, showed the similar response as the intestinal cells. These results suggest that studies of chemo-radiotherapy with cultured cells which are sensitive to chemotherapeutic agents might be suitable to expect the in vivo damage of the normal tissue.

One hundred and ninety-five episodes of fever during the neutropenic phase of chemotherapy in 49 patients with acute leukemia from 1984 to 1987 were analyzed with the following results: 1) Febrile episodes occurred in 80 percent of the neutropenic (less than 500/microliters) phase lasting more than 7 days after chemotherapy. 2) Febrile episodes consisted of 44 (22%) of established septicemia and 111 (57%) of suspected septicemia. 3) The pathogens causing septicemia were 8 GPC, 38 GNB (22 Pseudomonas species) and 6 fungi. Fungemia was confirmed on an average of 4.8 days after the onset of fever. The mortality of septic events was 10 out of 17 episodes (59%) when treated with antibiotics alone, while 8 out 27 (30%) with the combination of antibiotics plus antifungal drugs. 4) The mortality of suspected sepsis was only 2 out of 111 episodes. Eighty-three (75%) of these 111 episodes responded to antibiotics alone, while 26 (23%) cases needed antibiotics plus antifungal drugs. Our results suggest that in febrile neutropenic patient empiric broad-spectrum antibiotic therapy should be initiated which is especially effective for Pseudomonas species, but if fever persists despite more than 4 or 5 days of antibiotic therapy, additional antifungal therapy should be considered.

In order to determine the most effective anticancer agents for individual human tumor, succinic dehydrogenase inhibition test (SDI-T) and adenosine triphosphate inhibition assay (ATP-A) as in vitro chemosensitivity tests were performed. Fifty tumors and 57 tumors derived from cancer patients surgically methods were examined by SDI-T and ATP-A respectively. As the results, the evaluable rate was 70% by SDI-T and 94.7% by ATP-A, respectively. With SDI-T, the positive rate against all tumors was 51.4% in mitomycin-C (MMC), 42.9% in adriamycin (ADM), 20.0% in 5-fluorouracil (5-FU), 54.3% in cis-diamminedichloroplatinum (CDDP). On the other hand, with ATP-A, that was 20.4% in MMC, 29.5% in ADM, 20.6% in 5-FU, 20.4% in CDDP, respectively. Retrospective and prospective clinical trials were also carried out to determine the usefulness of both assays. With SDI-T, overall predictive accuracy rate was 57.1% while with ATP-A that was 88.9%. Furthermore, the rates of sensitivity for the same tumors using SDI-T and ATP-A were compared. The rate of the same sensitive cases in both assays were 30% with MMC, 70% with 5-FU, 42.1% with ADM, 36.8% with CDDP, respectively. In conclusion, it is suggested that ATP-A was more useful than SDI-T as in vitro chemosensitivity test to determine the most adequate drug for cancer patients.

Antitumor activity of a newly synthesized platinum complex, DWA2114R, by the serial administration was examined and compared with that of cis-diammine-1,1-cyclobutane dicarboxylato platinum (II) (CBDCA). In mice transplanted s.c. with tumor, the serial i.p. administration resulted in the increases of both maximal tolerated dose (MTD) and growth inhibitory ratio (GIR) of DWA2114R than single administration. Such increases in MTD and GIR were also shown by CBDCA, but the degree of these increases, such as the ratio of MTD or GIR by the serial administration compared to that at the single administration, was higher in DWA2114R than CBDCA. GIR of DWA2114R by the serial administration was higher than that of CBDCA at the doses to induce the same toxicity which was estimated by body weight loss. In addition, in the experiment using ascites tumor-bearing mice, better antitumor activity of DWA2114R was shown by the elongation of survival time. These results indicate that the cumulative toxicity of DWA2114R is lower than that of CBDCA, which causes the therapeutic advantages of DWA2114R in the serial administration.