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Purpose: The Japanese Foundation for Multidisciplinary Treatment of Cancer conducted a Phase I study of a novel oral fluorouracil derivative, S-1, combined with a low dose of cisplatin in unresectable and recurrent gastric cancer., Experimental Design: S-1 was administered orally at 80-120 mg/body/day, depending on body surface area. One course consisted of consecutive administration for 28 days followed by a rest of 14 days. Low-dose cisplatin was given i.v. on days 1-5, 8-12, 15-19, and 22-26 of each course. The dose escalation of cisplatin began with an initial dose of 1 mg/m(2)/day as level 1 and was stepped up to 2, 3, 4, and 6 mg/m(2)/day as level 2, 3, 4, and 5, respectively. The regimen was repeated for at least two courses., Results: A total of 24 patients was entered in the study. There was no treatment-related death. At level 5, consisting of 5 evaluable patients, dose-limiting toxicity was experienced as grade 3 appetite loss in 2 patients and grade 4 neutropenia in 1 patient. The maximum-tolerated dose of cisplatin was estimated to be 6 mg/m(2)/day. We decided on a recommended dose of cisplatin of 4 mg/m(2)/day because the dosage was one level under the maximum-tolerated dose. All 3 patients at level 4 showed partial response, suggesting promising clinical efficacy with this dosage. The serum concentration of cisplatin at level 4 was 918 +/- 92 ng/ml on day 26 of the first course., Conclusions: S-1 with low-dose cisplatin may become an effective regimen with acceptable toxicity for gastric cancer.

Background: Both docetaxel (TXT) and irinotecan (CPT-11) are active chemotherapeutic agents for gastric cancer. We designed a biweekly administration regimen of TXT combined with CPT-11 for 4 weeks as one cycle in patients with inoperable or recurrent gastric cancer, and conducted a dose-escalation study., Methods: Patients with histologically confirmed gastric cancer were treated with the regimen. The dosage levels of TXT and CPT-11 were as follows: level 1, 30 mg/m(2) and 50 mg/m(2); level 2, 35 and 50 mg/m(2); level 3, 40 and 50 mg/m(2); level 4, 40 and 60 mg/m(2); and level 5, 50 and 60 mg/m(2). The dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle., Results: Grade 4 neutropenia was observed at level 3, but no other DLT was observed at less than level 4 during the first cycle. However, three patients at level 3 could not continue treatment without a decrease in the dosage after the second cycle. Based on these results, level 2 was considered to be the clinically recommended dosages., Conclusion: Biweekly TXT and CPT-11 was well tolerated. The recommended dosages of TXT and CPT-11 for a phase II trial are 35 mg/m(2) and 50 mg/m(2), respectively.

Background: Because docetaxel and cisplatin are both active against gastric cancer and have different mechanisms of action, this combination may provide additive or synergistic effects against gastric cancer. This article presents a phase I study designed to determine the recommended dose of cisplatin combined with a fixed dose of docetaxel, and a subsequent phase II study that evaluated the clinical efficacy and feasibility of this combination regimen., Methods: Patients enrolled in the study had to have histologically confirmed advanced or recurrent gastric cancer with measurable disease and adequate organ function, and to be aged 20 to 75 years, with a performance status (PS) of 0 to 2. In the phase I study, docetaxel was administered at a fixed dose of 60 mg/m(2) on day 1. Cisplatin was also administered on day 1, at dose levels of 60, 70, and 80 mg/m(2). Where dose-limiting toxicities were not observed in more than 33.3% of patients, three patients were accrued for each dose level., Results: Recommended doses for the phase II evaluation were determined to be 60 mg/m(2) of docetaxel and 80 mg/m(2) of cisplatin. Although grade 3 or more severe leukopenia and neutropenia were observed in 71.4% and 82.1% of the patients, respectively, nonhematological toxicities were not severe. The overall response rate at the recommended dose level was 25.0% (7/28 patients), and the rate was 40% (6/15) for patients with liver metastases. The median survival time was 9.7 months and the 1-year survival rate was 39.3%., Conclusion: Although this study failed to demonstrate a high response rate, this regimen was feasible and might be of value in further investigations in respect to the relatively high response rate in patients with liver metastasis and the favorable survival.

Intravenously or intraperitoneally administered Chromomycin A3 (CHRM), an anticancer drug, augmented natural killer (NK) activity of both spleen cells and peritoneal exudate cells in BALB/c mice. When CHRM was administered intravenously, NK activity increased to about five fold that in nontreated mice on the 3rd to the 5th day, then rapidly decreased by the 7th day. On the other hand, when CHRM was administered by the intraperitoneal route, a peak of increased NK activity was observed on 5th to 7th day followed by a more gentle decrease. Augmentation of NK activity by CHRM was enhanced by additional administration of Interferon- gamma (IFN-gamma). Experimental evidence that NK activity could be augmented by CHRM in various strains of mice, independent of H-2 haplotype, suggested that involvement of genetic control within class I region of major histocompatibility complex could be excluded. When BALB/c mice inoculated subcutaneously with Meth A cells were treated with i.p. injection of CHRM, or CHRM in combination with IFN-gamma, the growth of the tumor cells was inhibited, indicating in vivo significance for the increased NK activity. Since this inhibitory effect was decreased by the injection of anti Asialo GM1 antibody (alpha-ASGM1), the effector cells presumably exerting killing activity against Meth A cells were concluded to be Asialo GM1 antigen positive.

The peripheral T lymphocyte subsets and natural killer (NK) cells of patients with cancer were studied by monoclonal antibody assays in comparison with those of non-cancer individuals. An imbalance of immunoregulatory T cell subsets was frequently found in the group of cancer patients (n = 26), being characterized by a relatively high proportion of OKT8+ cells (45.0 +/- 12.0%, p less than 0.01) and a low OKT4+/OKT8+ ratio (1.29 +/- 0.56, p less than 0.05). T cell level showed no significant difference as assessed by either OKT3 or rosette formation with sheep erythrocytes (E). The effect of bestatin was examined in 10 of these cancer patients. The relative proportion of T cell subsets tended to normalize 2 to 6 weeks after starting the daily doses of 30 mg per body. The mean percentage of OKT8+ cells decreased from 47.2 to 33.4 (p less than 0.01), while the helper to suppressor ratio increased from 1.18 to 1.79 (p less than 0.01). A significant increase was also found in the percentage and number of OKT4+ cells and HNK-1+ cells after the drug administration, while T cell level tended to converge to a normal range.

The proliferative response of the peripheral mononuclear cells (MNC) from cancer patients and healthy individuals to IL-2 was studied by use of the quantitative microwell assay of the 3H-TdR incorporation into the cells in vitro. After the addition of phytohemagglutinin (PHA), MNC acquired the reactivity to IL-2 within 3 hr, and reached a maximum after 12 to 17 hr of incubation. Although the IL-2 response of PHA-activated MNC from cancer patient was lower than that from healthy donor, there was no significant difference in the kinetics of proliferation. The maximum response of PHA-activated MNC from both cancer patients and healthy donors to IL-2 was observed at 96 hr and 84 hr, respectively. When monocytes were removed from MNC, IL-2-associated growth of the remaining fraction of MNC was decreased to 40-70% in both cancer patients and healthy donors. Furthermore, monocytes from cancer patients did not affect the IL-2 responsiveness of lymphocytes from healthy donors, and vice versa. The number of T lymphocytes having IL-2 receptors (IL-2R) from cancer patients was lower than that from healthy donors. These facts indicated that the lower IL-2 response of MNC from cancer bearer was due to the decreased number of T lymphocytes possessing IL-2R, and not due to monocytes themselves.