A feasibility study on the vibratory perception threshold (VPT) in normal volunteers was conducted to detect anti-cancer drug induced peripheral neuropathy. The VPT was found to increase with age. The mean VPT in the main hand in 25 normal volunteers was significantly higher than in the other hand. No variation of VPT was observed in one day or one week. Variation of VPT in the lower extremities was detected between two examiners. In conclusion, the measurement of VPT was expected to be useful for the detection of anti-cancer drug induced peripheral neuropathy, if there is one examiner and the examined hand is specified.

Fifty-three patients with advanced colorectal cancer were given single oral doses of 5'-DFUR, 400 mg/body, preoperatively to assess the pharmacokinetics of 5'-DFUR in the patients with colorectal cancer and to investigate schedules for 5'-DFUR treatment. The time courses of PyNPase activity and 5-FU concentration in the resected tissue specimens were determined. This study indicated that: 1) High 5-FU concentration and PyNPase activity were noted in tumor tissue and lymph nodes. 2) Effective 5-FU concentration in tumor tissue was maintained even 24 hours after treatment. 3) Effective lymph node concentration of 5-FU was maintained even 8 hours after treatment. 4) PyNPase activity in tumor tissue was significantly higher than that in the normal intestinal mucosa (p < 0.05). These results suggest that 400 mg of 5'-DFUR at 8-hour intervals provides effective tissue concentrations of 5-FU for the treatment of patients with advanced colorectal cancer.

There are many studies in the literature on the subject of anti-neoplastic drugs for acute and chronic cardiac toxic function. It is important to check previously the cardiac toxicity of the new anti-neoplastic drugs. Now we have had a chance to study the first stage examination of RA-700, isolated from Rubia akane or Rubia cordifolia. Then we tried to study several kinds of parameters, for instance ECG, ultrasonic cardiograms and arterio-grams on cardiac toxicities of RA-700. We injected the first group of neoplastic patients only once with RA-700, while in the second group, we injected them with RA-700 for 5 consecutive days (see our previous report.) In the present study, we made some conclusions about the administration of RA-700. 1) Changes in cardiac function were noted in both groups. 2) Changes in blood pressure, sigma QRS, ejection fraction, and fractional shortening of the second group tended to be more extreme than those of the first group. Care for continuity is a concern with long-term and high doses of RA-700. 3) Because of the small sample, we could find no relationship between the changes in cardiac function and the injection doses of RA-700. 4) Therefore, the cardiac function must be checked by giving anti-neoplastic drugs to neoplastic patients.

Phase I study on a new vinca alkaloid derivative, KW-2307(vinorelbine), was conducted by multiple institutions in 40 patients with a variety of malignant tumors. KW-2307 was given intravenously by single administration or by weekly repeated for 4 weeks (hereinafter as the repeated administration). The initial dose, 10 mg/m2(ln), was escalated to 35 mg/m2(3.5n) in single administration and to 30 mg/m2(3n) in the repeated administration. A total of 35 cases were eligible for evaluation, consisting of 18 cases in single administration group and 17 in the repeated group. Both of single and repeated administration caused leukopenia dose-dependently, and the dose limiting toxicity (DLT) was judged as leukopenia. The maximum tolerated dose (MTD) was 30 mg/m2 in single administration and 25 mg/m2 in the repeated administration provided that administration is made weekly for 4 consecutive weeks. As subjective and objective adverse effects, general fatigue, anorexia, constipation, phlebitis etc. were observed, but all of these symptoms were relatively mild and recoverable. Peripheral neuropathy were found in two cases and judged as Grade 1. In this phase I study, a tendency of the decrease in tumor size was seen in 3 cases; 2 of non-small cell lung cancer and 1 of breast cancer. The pharmacokinetics of KW-2307 in blood after single administration showed a triphasic disappearance pattern with half-life of about 20 to 60 hrs. The data of pharmacokinetics after repeated administration revealed no accumulation of this agent. The recommended dose for early phase II study was supposed to be 20 to 25 mg/m2/week.

We reviewed recent reports on apoptosis and summarized the presentations at the Shirafu Cancer Symposium, 1993. The study of programmed cell death, apoptosis, has become one of the mainstream in cell biology, particularly in immunology, developmental biology and oncology. To determine whether the apoptotic cell death induced by anti-cancer agents could be inhibited by bcl-2, we established a bcl-2-transfected human small cell lung cancer cell line, SBC-3/Bcl-2. SBC-3/Bcl-2 showed higher resistance to ADM, CPT-11 and MMC compared with the parental line SBC-3. Agarose gel electrophoresis showed typical DNA fragmentation of SBC-3 following treatment with CPT-11 or MMC. In contrast, the same concentration of the drugs did not induce DNA fragmentation in SBC-3/Bcl-2. However, there was no difference in sensitivity to CDDP, VP-16, ACNU, MTX and Taxol between SBC-3 and SBC-3/Bcl-2 (Ohmori, T. et al. Biochem. Biophys. Res. Commun. 1993). These studies indicate that bcl-2 can modulate the cytotoxicity of some anti-cancer agents by inhibiting the process of apoptosis. We speculate that some apoptotic pathways are bcl-2-sensitive and others bcl-2-independent.

Metallothionein (MT) shows a protective effect against toxic actions of some antitumor drugs and gamma-irradiation in animals. Preadministration of bismuth subnitrate, an MT inducing drug, significantly reduced side effects of antitumor drugs without affecting antitumor activity of the drugs. This specific effect of bismuth on the toxicity of antitumor drugs appears to be attributable to its specific induction of MT in normal tissues, but not in tumor tissue. Preinduction of MT synthesis in the lung also prevented mice from carcinogenesis caused by cisplatin and melphalan in the lung. On the other hand, zinc compound induced MT synthesis in the tumor, and significantly suppressed the antitumor activity of some antitumor drugs. Propargylglycine (PPG), an inhibitor of cystathionine pathway, significantly inhibited MT induction by zinc in the tumor inoculated in mice, and, consequently, PPG could diminish cisplatin resistance acquired by an increase in the tumor MT levels.

The antitumor effect of a new derivative of taxol, docetaxel (RP56976), was examined in K562 human tumor system in vitro. K562 cells presenting a multidrug resistant phenotype showed cross resistance to docetaxel. However, the resistance levels of docetaxel in these cell lines were much lower than for adriamycin and vincristine. Flow cytometric analysis showed the accumulation of cells into G2/M phase after 18hrs. Wright-Giemsa staining showed a marked increase of metaphase population. Docetaxel was shown to promote the assembly of microtubule protein without GTP in vitro, but no inhibitory effect on DNA, RNA and protein synthesis. Moreover, topoisomerase activities were not affected by docetaxel. These results indicate that docetaxel acts as a strong mitotic inhibitor in cancer chemotherapy.

Neovascularization is critical for the growth of tumors and is mediated by physiological substances produced by the tumors. Vascular endothelial growth factor (VEGF) is one of such potent angiogenic factors. We evaluated VEGF gene expression on urinary bladder carcinoma and renal cell carcinoma by Northern blot analysis and demonstrated that VEGF was frequently overexpressed in renal cell carcinoma, in up to 67% of patients, but not in urinary bladder carcinoma. These results suggested that VEGF was produced by renal cell carcinoma and is responsible for the hypervascularity of this tumor. TNP-470, an angiogenesis inhibitor, is a new type of anticancer drug that inhibits tumor neovascularization. We evaluated the antitumor effect of TNP-470 in mice bearing B-16 melanoma or Lewis lung carcinoma. TNP-470 at a dose of 20 mg/kg body weight inhibited growth of both tumors. The degree of antitumor effect exerted by TNP-470 was greater than that of ADM (2.5 mg/kg body weight) and as great as that of MMC (2.5 mg/kg body weight). Combination of TNP-470 with MMC enhanced the antitumor effect. Monitoring of mouse body weight did not reveal any significant changes among the treatment groups, indicating that systemic toxicity of TNP-470 was not severe. These results suggested that TNP-470 was effective for the treatment of solid tumor by inhibiting its neovascularization.

Preclinical and clinical studies have demonstrated the effectiveness of granisetron in preventing emesis induced by antineoplastic chemotherapy. This comparative study was undertaken to investigate the efficacy and safety of granisetron (40 micrograms/kg) and granisetron plus methylprednisolone (MPL; 10 mg/kg). Sixty-eight patients were given granisetron 170 times and thirty-nine patients were given a combination of granisetron and MPL 81 times. Sixty-one patients received the treatment in crossover fashion during the same chemotherapy regimens. The emetic and nausea episodes were counted during the 24 hours following each chemotherapy treatment. Complete response, no emesis or less than two episodes, were obtained in 75.3% (128/170 times) of patients receiving granisetron alone compared to 85.2% (69/81 times) of patients receiving the combination of granisetron plus MPL. There were no significant differences in complete responses between the two groups, male and female, and each age group. However, 11 of eighteen patients receiving granisetron alone who responded mildly, if at all, with respect to nausea and vomiting, showed a complete or major response when MPL was added to granisetron. There were two patients who developed temporal paresthesia of the both hands as an adverse effect, but there was spontaneous recovery after 3 hours. Our data suggested that granisetron plus MPL was slightly more effective than granisetron alone and a safe antiemetic drug.

An early phase II study of irinotecan (CPT-11) in patients with advanced or recurrent breast cancer was undertaken by a cooperative study group of 15 institutes in Japan. CPT-11 was administered by intravenous drip-infusion. The administration schedules were 100 mg/m2 weekly (regimen A), 150 mg/m2 biweekly (regimen B), and 200 mg/m2 every 3-4 weeks (regimen C). There were 4 partial responses (PRs), 12 cases with no changes (1 minor response) and 9 cases of progressive diseases with a response rate of 16% (4/25). One out of 7 patients on regimen A and 3 patients out of 15 patients on regimen C achieved PR with a response rate of 14% and 20%, respectively. In three out of 4 PRs, prior chemotherapy, endocrinotherapy or radiotherapy had failed. Major adverse reactions were leukopenia 28/33 (85%), neutropenia 19/25 (76%), anemia 15/33 (46%), nausea/vomiting 28/33 (85%), anorexia 25/33 (76%), diarrhea 22/33 (67%) and alopecia 20/33 (61%). The incidence of leukopenia and thrombocytopenia seemed to be higher in regimen C than regimen A, and diarrhea was also more severe in regimen C than regimen A. The recovery of leukopenia was delayed in some patients on regimen C. The results suggested that CPT-11 was effective against advanced or recurrent breast cancer. The recommended administration schedule for a late phase II study was thought to be 100 mg/m2 weekly, considering efficacy and safety.

An early phase II study of CPT-11 (irinotecan hydrochloride) was conducted in patients with hematological malignancies by 4 administration regimens in a cooperative study involving 13 institutes in Japan. The overall response rate was 23% (7/30) for non-Hodgkin's lymphoma, 33% (1/3) for Hodgkin's disease, 18% (2/11) for acute lymphoblastic leukemia and 7% (1/15) for acute myelogenous leukemia. One PR was also obtained in a patient with chronic myelogenous leukemia. Among responders, 6 relapsed and refractory malignant lymphomas (ML) and 2 relapsed and refractory acute leukemias (AL) were involved. The response rates in ML with the regimens B (40 mg/m2 for 5 days every 3-4 weeks) and C (40 mg/m2 for 3 days every weeks) were 31% (5/16) and 33% (3/9), respectively. The other regimens (regimen A, 200 mg/m2 once a day every 3-4 weeks and regimen D) resulted in no response. Responses in AL were only observed in regimen D (20 mg/m2 twice a day for 7 days every 3-4 weeks). Major toxicities were leukopenia (91%), nausea/vomiting (74%), diarrhea (73%) and anorexia (64%). The incidence of severe gastrointestinal symptoms was higher in regimen B than regimen C. Further studies are warranted to confirm the effectiveness and safety of CPT-11 against ML and AL. The recommended administration schedule was regimen C for ML and regimen D for AL.

Rhodamine 123 (Rh123) is a red fluorescence dye, which is accumulated more and retained longer in the mitochondria of malignant transformed cells. In this study, the suppressive effects on the growth of cultured urogenital carcinoma cells (PC-3 and LNCaP from prostate carcinoma, T-24 from bladder cancer, and SV-HUC-1 human ureteral transitional cell transformed by SV virus in vitro, ACHN, YCR-1 and RCF213 from renal cell carcinoma) were examined. The cell growth of PC-3, LNCaP, T-24 and SV-HUC-1 was suppressed significantly in a dose dependent manner, but that of cells derived from renal cell carcinoma was not suppressed. The uptake and elimination of Rh123 in PC-3, ACHN and YCR-1 were not significantly different. When administered with verapamil and buthionine sulfoximine, which are reported to be chemical modulators of anticancer agents, Rh123 suppressed the growth of ACHN and YCR-1 significantly. Rh123 seems to have an anticancer effect against the urogenital carcinomas, and the role of Rh123 with hyperthermia, photodynamic therapy and chemotherapy requires further investigation.

The present study was designed to evaluate the antiproliferative effects of suramin and the combination of suramin plus cisplatin (CDDP) on the hormone-independent human prostate carcinoma cell line (PC-93). In vitro, suramin induced a dose-dependent reduction of PC-93 proliferation, and at the clinically achievable concentration (300 micrograms/ml), suramin induced a 19.7% decrease in proliferation on the 3rd day compared to suramin-free control (P < 0.01). However, from the 4th day on the inhibitory action of suramin was reversed following exposure. The suramin-cisplatin combination showed an additive effect (inhibition ratio 32.4% on the 3rd day), and prolongation of the inhibition activity on the 4th day on, but it did not show any synergistic effect. Suramin inhibited dose-dependently the growth stimulatory effect of exogenous epidermal growth factor (EGF). In vivo study, suramin and suramin-cisplatin combination showed antitumor effects continuously in nude mouse implanted PC-93. These findings suggest that the inhibitory effects of suramin on PC-93 are mediated by inhibition of the EGF-mediated growth mechanism, but by a cytostatic rather than cytotoxic manner in vitro. In addition, other mechanisms such as inhibition of angiogenesis factor might exist in vivo.

DNA topoisomerases are enzymes involved in various aspects of genetic processes by catalyzing a topological change of DNA. Topoisomerase is now viewed as an important cellular target of antitumor drugs. These drugs targeting topoisomerase have been used to establish a relationship between drug-induced cleavable complex formation and cytotoxicity. Topoisomerase I is shown to be the cellular target of camptothecin and its derivatives. And topoisomerase II targeting drugs are both intercalative drugs (acridines, ellipticines, anthracyclines) and non-intercalative drugs (epipodophyllotoxin derivatives). And then Irinotecan, topotecan, sobuzoxane and IST-622 are unique topoisomerase inhibitors and are under investigation in Japan, the new antitumor drugs targeting topoisomerases are reviewed.

This paper described an outline of clinically applications of 5-HT3 receptor antagonists, mainly on ondansetron, which control nausea and vomiting associated with cancer chemotherapy. Clinically, 5-HT3 receptor antagonists demonstrated significantly superior antiemetic effects to metoclopramide which has been prescribed for relatively long time. The response rates for granisetron and those for ondansetron were different due to the different categorical scales. However, when the same scale was applied, similar efficacies have been observed. Introduction of the tablet form may well broaden the clinical applications. Considering the highly evaluated safety, 5-HT3 receptor antagonists, from the viewpoints of clinical usefulness and safety, seems to be useful drugs for controlling nausea and vomiting associated with cancer chemotherapy.

This paper described an outline of pharmacological studies of 5-HT3 receptor antagonists, mainly on ondansetron, which control nausea and vomiting associated with cancer chemotherapy. Administration of cytotoxic drugs is known to increase serotonin (5-HT) concentrations, and when released, 5-HT provokes the emetic responses via two routes; 1) 5-HT acts as an intrinsic transmitter substance and stimulates the emetic response via 5-HT3 receptors on vagal afferent terminals; 2) 5-HT transmits impulses to the vomiting center via 5-HT3 receptors on the chemoreceptor trigger zone in the area postrema of the central nervous system. 5-HT3 receptor antagonists are thought to exert an antiemetic action by specifically and competitively blocking 5-HT3 receptors.