Phase I study with a new oral anticancer agents. MST-16 (Sobuzoxane), was conducted by 3 administration schedules: single, 5 consecutive days and 10-15 consecutive days. No toxicity was observed in the single administration at doses escalated up to 1,500 mg/m2. Dose-dependent leukopenia was observed from 560 mg/m2/day in consecutive 5 day administration, and median days to the nadir and recovery were about 2 and 1 week, respectively. GI-disorders were also observed sporadically from 800 mg/m2/day. One patient with Hodgkin's disease receiving 1,000 mg/m2/day achieved complete response. Consecutive administration for 10-15 days was carried out at a dose of 800 mg/m2/day. Six out of 7 evaluable patients demonstrated leukopenia, and all 2 patients treated for 15 days experienced leukopenia with a nadir corresponding to grade 3. Median days to nadir and recovery were both about 2 weeks. Doses recommended for phase II study were considered to be 1,600 mg/body/day for 5 days and 1,200 mg/body/day for 10-14 days.

We evaluated the subrenal capsule assay with a chemosensitivity test using 47 fresh surgical explants, including 16 renal cell carcinomas and 10 uroepithelial cancers. Forty-one explants were evaluable and 166 drug tests were performed. Forty-seven tests (28.3%) were found to be sensitive. Ten of 16 renal cell carcinomas involved a sensitive drug, 3 involved more than 2 sensitive drugs. VP-16, ADM, BLM and 5-FU were the most sensitive compared with the others. Concerning the uroepithelial cancers, 8 of 10 involved a sensitive drug, 5 involved more than 2 sensitive drugs. CDDP and VP-16 were more effective than the other drugs. This result showed a good correlation with the clinical therapeutic efficacy using CDDP. In the future, we hope to evaluate the clinical correlation between clinical efficacy and this assay.

Cardiotoxic effects of ME2303 were studied upon interval intravenous administrations to rats in comparison with those of doxorubicin (ADR). ME2303 at two dose levels of 3 and 9 mg/kg/day or ADR at a dose levels of 3 mg/kg/day was injected once a week for 3 weeks to female Sprague-Dawley rats (SPF) of 5-weeks of age. ADR depressed body weight gain, decreased food intake and increased water intake. Microscopic observation on the myocardial tissues revealed that ADR caused necrosis and cell infiltration, edema and disarrangement of myofibrils in some of ADR-treated rats. On the other hand, ME2303 showed no significant effects except that some decrease of food intake was observed at a dose level 9 mg/kg/day. No changes in left ventricular functions were observed in perfused hearts isolated from ADR- or ME2303-treated rats. However, about 133 ng/g of ADR remained in the hearts even at 1 week after the final administration whereas ME2303 or its metabolites were not detected, suggesting that ADR may cause disturbance of ventricular function and more cardiomyopathy after a longer term than 1 week following the final administration. These results suggest that the cardiotoxicity of ME2303 is weaker than that of ADR in rats.

The purpose of this study is to assess the lethal and kinetic effects of CDDP, ADM, MMC and 5FU on human gastric cancer cell lines, MKN28, MKN45 and KATO III. The lethal effect was examined by growth inhibition test and colony forming test. The DNA content and DNA synthesis rate of individual cells were simultaneously measured by DNA/BrdU double staining method. In growth inhibition test, MKN45 was sensitive to CDDP, and all cell lines were sensitive to ADM, MMC and 5FU. On the other hand, in colony forming test, these cell lines were sensitive to all drugs. In the cell kinetics, CDDP, ADM and MMC yielded a significant increase of G2 phase fraction at 24, 48 and 72 hours, and caused a significant decrease of BrdU labeling index at 48 hours. The changes of G2 phase fraction and BrdU labeling index were correlated well to the lethal effect of CDDP, ADM and MMC. However, 5FU did not cause these changes to the cell lines employed in the cell kinetic study. Therefore, it was suggested that these results of the cell kinetics might be applied to anticancer agent sensitivity test by selecting adequate anticancer drugs.

In treating brain tumors with chemotherapy, the choice of drug is most important since human tumors have different drug sensitivities and growth rates. We have been studying the therapeutic effect of anticancer drugs against malignant brain tumors in the following in vivo models. 1) Human glioma-bearing nude mice. 2) Methylcholantrene-induced 203Gl mouse glioma-bearing immunocompetent C57BL/6 mice. 3) Human gliomas transplanted into the chorioallantoic membrane of chick embryos. We evaluated the advantages of each model for anti-cancer drug sensitivity tests. 1) Human glioma-bearing nude mice were found to be most useful in predicting the direct effects of anticancer drugs. We evaluated the effects of several drugs such as ACNU or interferons in six glioma strains transplanted into nude mice. 2) Immunocompetent C57BL/6 mice models were found useful in predicting the therapeutic effects of biological response modifiers. In this model, we can also evaluate changes in immunological parameters such as NK activities or T cell subsets. 3) In the drug sensitivity test using the CAM of chick embryos, various kinds of gliomas could be grafted with a high rate of success. The tumor reduction rate of the sensitivity test using this system tended to agree with that using nude mice. This test was found to be useful in predicting the effect of drugs against gliomas directly resected from individual patients.

Transcatheter hepatic arterial embolization (TAE) with gelatin sponge particles soaked in anticancer agents has been widely employed in the treatment of Hepatocellular carcinoma (HCC). The mechanism of TAE has been explained by blocking of blood flow to the tumor, however the role of anticancer agents used with embolic materials has remained unclear. The purpose of this study is to prove the role of anticancer agents used in TAE. 1) In eighteen cases of HCC and 4 cases of metastatic liver cancer, TAE was performed with gelatin sponge, anticancer agents and contrast media. The livers were examined by CT 4, 24 and 48 hours after TAE. A selective retention of contrast media containing anticancer agent in the tumor area was observed in 14 of 14 cases examined 4 hr. in 15 of 17 cases examined 24 hr and in 6 of 6 cases examined 48 hr after TAE. In the cases of metastatic liver cancer, retention of contrast media, was also observed in 4 of 4 cases examined at 24 hr and 3 of 3 cases examined 48 hr after TAE. 2) TAE was done in 12 cases of HCC by using gelatin sponge soaked in anticancer agent mixed with 99M-Tc-pertechnetate. Livers were observed by a scintillation camera 4 hr and 24 hr after TAE. A selective retention of 99M-Tc-pertechnetate in the tumor was observed in 12 of 12 cases examined 4 hr and in 3 of 3 cases examined 24 hr after TAE. 3) In one cases of HCC, hepatectomy was performed 2 days after TAE.(ABSTRACT TRUNCATED AT 250 WORDS)

A new 5-fluorouracil (5-FU) derivative, BOF-A2 (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl)benzoyl]-1- ethoxymethyl- 5-fluorouracil), is consisted of EM-FU (1-ethoxymethyl-5-fluorouracil) which is specifically and gradually converted to 5-FU by the drug-metabolizing enzyme of liver microsomes and CNDP (3-cyano-2,6-dihydroxypyridine), a potent inhibitor of 5-FU degradation in the liver. When BOF-A2 was given orally, blood levels of the main metabolites, EM-FU and CNDP, were maintained for a longer time in the tumor-bearing rats, and eventually the blood 5-FU levels were maintained over 12 hours. Moreover, 5-FU levels in the tumor tissue tended to be maintained higher and longer time over 24 hrs. than those in the blood of rats. Antitumor activity of such characterized BOF-A2 was investigated with transplantable tumors in rodents and DMBA-induced breast carcinomas in rats. The ED 50 (the dose for 50% inhibition of tumor growth) value was about 15 to 25 mg/kg against the tumors tested. These result may suggest that BOF-A2 has potent antitumor activity in accordance to the long persistence of 5-FU level in the tumor tissue.

Fundamental evaluation of the subrenal capsule assay (SRCA) method in nonsolid tumors was made, using two types of murine malignant ascites. Malignant ascites were obtained from mice bearing M-5076 ovarian reticular cell sarcoma or MH-134 hepatoma. These tumor cells were allowed to settle by standing at 4 degrees C to form a jelly-like clot. This clot was cut into fragments about 1mm3 in size and one of these fragments was mashed in trypan blue to estimate the viability grade of the implanted tumor cells. The rest of the fragments were implanted beneath the renal capsule of the mice. On the 6th day after implantation, the assay mice were killed, the increase in the size of the tumor was determined and histological examination was carried out. The results were as follows: (1) The clot was formed reproductively by allowing ascites to settle for one or two days and there was a high viability rate for the tumor cells: 79.9 +/- 11.0% of M-5076 and 90.1 +/- 5.9% of MH-134. (2) The ascites clot thus implanted grew rapidly in the control groups but growth was inhibited by chemotherapy: Tumors were reduced significantly (p less than 0.05-0.005) in the group treated with a single agent. This trend towards a suppressive effect of carcinocidal agents on the tumor growth was more conspicuous as a combination regimen was utilized, a combination of three agents producing the maximum effect. (3) The clot grew more quickly than the solid tumor in both the control and the treated groups. There was a high correlation (r = 0.93 in M-5076, and r = 0.64 in MH-134) between the growth rates of ascites and solid tumor in SRCA. (4) Histological examination revealed that viable tumor cells infiltrated widely under the renal capsule in both types of tumors. These results suggest that ascites and solid tumor are useful materials for the subrenal capsule assay method.

A clinical study of weekly administration of CPT-11, a semi-synthetic derivative of Camptothecin, was performed in patients with advanced lung cancer to determine the optimal dose for a weekly single dose schedule. Sixteen out of 19 patients enrolled were evaluable. The starting dose was 50 mg/m2 and gradually escalated to 100, 125 and 150 mg/m2. CPT-11 was given by intravenous infusion for 90 minutes every week. The maximum tolerated dose for this schedule was estimated to be 125 mg/m2. The dose-limiting toxicity was leukopenia with median nadir of 2,900/mm3, median day to nadir of 21, and median day to recovery of 7. Other major toxicity was gastrointestinal upset, but was mild and tolerable. Objective tumor responses were observed in four patients, three with non-small cell carcinoma and one with double cancer (small and non-small cell carcinoma). The responding patients were treated at a dosage of 100 mg/m2 or more. The recommended dose for a phase II study is considered to be 100 mg/m2 iv infusion for a weekly single-dose schedule.

A subrenal capsule assay (SRCA) was performed to test the sensitivity of 45 gynecological malignancies, including 24 cervical and 15 ovarian carcinomas, to oral antitumor agents, UFT, cyclophosphamide (CPM) and carboquone (CQ). Additionally, using a human endometrial carcinoma (Ishikawa carcinoma), the utility of SRCA in oral adjuvant chemotherapy was also investigated. Thirty-six of 45 cases (80.0%) were found to be evaluable. Regardless of the origin or of the histological type, each gynecological tumor showed a different degree of sensitivity. The results suggested that it is necessary to choose an oral antitumor agent according to the degree of sensitivity in oral adjuvant chemotherapy. In an experimental study with an implanted tumor, 14 of 20 mice (70.0%) developed a recurrent tumor in the control group. Compared to this, the recurrence rates for tumors in mice treated with CPM, CQ and UFT were 10.0% (p less than 0.001), 25.0% (p less than 0.01) and 30.0% (p less than 0.02), respectively. All these agents were considered to be effective in preventing tumors from recurring. In SRCA, the implanted tumor was sensitive to CPM and CQ, but not sensitive to UFT. These data suggested that SRCA is useful in predicting the effect of dose-dependent agents in oral adjuvant chemotherapy, although, with UFT, a time-dependent agent, it is not clear whether SRCA is appropriate for estimating the usefulness of its agent.

Recently, the quality of life of a cancer patient has been extensively discussed. Especially, side effects of chemotherapy are major problems of cancer patients. Cardiotoxicity of adriamycin and pulmonary toxicity of bleomycin are not common side effects of chemotherapy, but they can be devastating, particularly, when they occur in a patient who has been cured of cancer. Therefore, we tried to demonstrate the efficacy of cardiac or pulmonary monitoring in early detection of the toxicity. In conclusion, now non-invasive and invasive standard methods of monitoring have yet to be convincingly established, because most methods are either of no predictive value or too sensitive. Moreover, to date an effective prophylaxis of cardiotoxicity or pulmonary toxicity is still lacking. Exact evaluation of risk factors and thorough cardiac or pulmonary monitoring are necessary in patients under chemotherapy.

In a cross-over design of a study of prevention of emesis induced by cancer chemotherapy done in Saitama Cancer Center, the efficacy of oral lorazepam was superior to that of i.v. domperidone. And then, we proceeded a parallel study with use of oral lorazepam and oral domperidone. However, in this situation lorazepam was not superior to domperidone despite accrual of more than 60 patients. Recently, a multi-institutional study has been started in October of 1988 in an evaluation of the efficacy and safety of the new anti-emetic drug of a 5HT3 receptor antagonist, ondansetron. Two methods of its administration were designed. In one study ondansetron was given 2 hr prior to non-platinum chemotherapy as an 2 or 8 mg dose by oral administration, followed by receiving it 6 hr and 12 hr after chemotherapy. In another study, it was given 15 min prior to cisplatin including chemotherapy as an 2 or 8 mg loading dose by i.v. injection over 5 min, followed by continuous infusion at a rate of 0.25 mg/h or 1 mg/h for 24 h, respectively. Efficacy was assessed by measurement of the number of episodes of retching and vomiting occurring in the 24h after administration of chemotherapy and by an assessment of nausea during the same period. This time the major efficacy category was adopted, which is made up of the complete responder and major responder categories of both vomiting and nausea. 19 patients were evaluable for efficacy in the non-platinum group; the major efficacy rates showed 45% in 2 mg-given group and 88% in 8 mg-given group, respectively. 108 patients were evaluable for efficacy in the cisplatin group: the major efficacy rates showed more than 70% in both 2 mg and 8 mg-given group. However, in the patients given more than 75 mg/mg2 of cisplatin, the major efficacy rates were 55% in the 2 mg-given group, compared to 73% in the 8 mg-given group. Ondansetron was well tolerated, with no significant drug-related adverse events.

Renal dysfunction and urinary disorders are the most troublesome adverse reaction to anticancer agents such as cisplatin (CDDP) and ifosfamide (IFM). A number of antidotes such as sodium thiosulfate (STS), WR-2721, thiourea, diethyldithiocarbamate and bismuth subnitrate have been tested to reduce the nephrotoxicity of CDDP. One notable method previously reported by Baba et al. and Pfeifle et al involves the i.v. administration of STS to prevent the nephrotoxicity of CDDP given locally. Since STS has been proven clinically effective in reducing such side effects, we initiated a study of STS in patients with advanced non-small-cell lung carcinoma who were given a combination of CDDP and vindesine (VDS) systemically. Urinary levels of beta 2-microglobulin (BMG) and N-acetyl-beta-D-glucosaminidase (NAG) were measured as an index of proximal tubular function. Analysis of both levels indicated that STS suppressed CDDP nephrotoxicity to a minimal level. Therefore, the present study clearly demonstrates that systemic administration of STS reduces the side effects of CDDP to a minimal level without impairing its antitumor activity and that STS treatment is applicable in a repeated chemotherapy using CDDP alone or in combination with other antitumor agents. Furthermore, it has been reported that urinastatin and fosfomycin may exert potent effects to reduce untoward nephrotoxicity of CDDP. IFM causes urinary disorders such as hematuria, reducing its clinical usefulness, Sodium 2-mercaptoethane sulfonate (mesna) is the thiol compound which binds specifically to the urinary toxic metabolites of IFM, and thereby decreases the undesirable effect of IFM on the lower urinary tract, especially on the bladder. Recently, it was reported by a Osaka mesna study group that mesna is useful for the prevention of IMF-induced urinary disorders. It was considered that above new treatments were required in repeating chemotherapy which induced urogenital toxicity.

MTT assay was performed simultaneously with a clonogenic assay to assess its validity on chemosensitivity test by using the cultured human urogenital carcinoma cell lines PC3, 19PC93, DU145 and T24. The drugs used were carboquone (CQ), adriamycin (ADM), cisplatin (CDDP) and pepleomycin (PLM). Dose response curves were drawn and 50% inhibition doses (ID50) were calculated and examined by t-test. The correlations between the results obtained from both assays were observed. For comparing antitumor intensity of drugs with each other, predicted antitumor activity (PAA) was calculated from the peak plasma concentration of the clinically used dose. High cytotoxicity of drug was considered if PAA greater than or equal to 1 was observed. The optical density (OD) was almost directly proportional to the number of cells. Good correlations between OD and colony number, or between ID50 from both assays were noted although the clonogenic assay is more sensitive than the MTT assay. Relative resistances between cell lines to a drug observed by the clonogenic assay were also maintained by the MTT assay. The chemosensitive intensity was CQ greater than ADM greater than CDDP greater than PLM, and the sequence was similar in both assays. PC3, DU145 and T24 were sensitive to CQ but 19PC93 was to CQ and ADM. Therefore, MTT assay was concluded as a useful method for chemosensitivity test, although the problem of normal cell contamination was left to be solved for clinical use.