A dose-escalation and pharmacokinetic study of subcutaneously administered recombinant human interleukin 12 and its biological effects in Japanese patients with advanced malignancies.

A pilot dose-escalation study of recombinant human interleukin 12 (rhIL-12) was conducted in Japanese patients with advanced malignancies. Cohorts of three patients received escalating doses of rhIL-12 that increased from 50 to 300 ng/kg/day s.c. three times a week for 2 weeks followed by 1-week rest. The same dosage and schedule was repeated for two additional courses. Sixteen previously treated patients were registered, and 15 were evaluated. Common toxicities were fever and leukopenia; the abnormality of laboratory tests included elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, C-reactive protein, and beta2-microglobin. Dose-limiting toxicity was the grade 3 elevation of aminotransferases, and was observed in two of six patients at the 300-ng/kg dose level after the first course in one patient and after the third course in the other. Leukopenia was observed at all of the dose levels; two of six patients at 300 ng/kg experienced grade 3 leukopenia. Thus, 300 ng/kg was determined to be the maximum acceptable dose. Peak plasma levels of rhIL-12 decreased in the second courses, but the areas under the curve were almost the same in the first and second courses. Biological effects included increases of plasma levels of IFN-gamma, tumor necrosis factor-alpha, IL-6, IL-10, and neopterin. In two patients with renal cell carcinoma, complete response and partial response of metastatic tumors were observed with 50 and 300 ng/kg; the responses lasted for 5 and 3.5 months, respectively. Although immunological response to rhIL-12 varies depending on administration route and schedule and on patients' physiological conditions, the recommended dose for Phase II studies is 300 ng/kg s.c. three times a week for 2 weeks followed by 1-week rest.

A comparative study for fiberoptic and video endoscopic determination of the extent in minimal changes of gastric mucosa using indigo dye spraying.

The image resolution of fiberoptic and video endoscopy was compared in a series of patients with early gastric cancer. Eighteen patients were divided into two groups. One group of patients (n = 9) was evaluated with fiberoptic endoscopy while the second group (n = 9) was evaluated using video endoscopy. The extent of cancer invasion, with special attention to size, shape and type of the lesions, was evaluated in each patient. Attempts were also made to identify the proximal and distal limits of tumor invasion and the endoscopic and postoperative findings were compared. Endoscopic delineation of lesions was possible in more patients undergoing video endoscopy compared to fiberoptic endoscopy. Video endoscopy gave better endoscopic images for determination of the limits and of the size of cancer invasion. Indigo dye spraying enhanced the accuracy rates in both groups of patients. The results of this study suggest that video endoscopy may be more useful than fiberoptic endoscopy in the evaluation of minimal mucosal changes of the gastrointestinal tract. We believe that video endoscopy may have a useful role in the gastrointestinal endoscopy if the problem of expense, which is its main drawback, can be solved.

Development of an interleukin-2 slow delivery system.

The authors developed a slow delivery system for interleukin-2 (IL-2) using highly purified bovine collagen to overcome the rapid clearance and side effects of IL-2; 1 X 10(6) microns of recombinant human IL-2 was successfully infused into needle-shaped "IL-2 mini-pellets". Pharmacokinetic study in C57BL/6 mice revealed that a single subcutaneous injection of an IL-2 mini-pellet could prolong IL-2 retention and decrease maximal concentration in the serum. Elimination half-life was 360 min for subcutaneously injected IL-2 mini-pellets, while it was 8 and 15 min, respectively, for intravenous and subcutaneous injections of aqueous IL-2. No side effects were observed throughout the experiment. This slow delivery system using collagen as a carrier proved to be effective and may be applicable to other kinds of drugs.

[The immune defense system in gastric cancer tissue, regional lymph node and spleen--aspects from subsets and functions of lymphocytes].

Tumor infiltrating lymphocytes (TIL) and lymph node lymphocytes (LNL) were thought to play an important role in local immunity against cancer. But the natural cytotoxicity (NC) of TIL and LNL was very weak, and was not augmented by beta-IFN. This low cytotoxicity was augmented by IL-2, and especially LNL were activated to have higher lymphokine activated killer (LAK) activity than that of PBL. So it was proven that TIL and LNL had an potential of immunological defence system. In order to bring out these potential, immunomodulators (OK-432, PSK) were injected intralesionally under endoscopy one week prior to surgery. The cytotoxicity of TIL and LNL was augmented by the intralesional injection of OK-432 or PSK. There was no significant difference in LAK activity of LNL among the OK-432-, PSK-injected group, and the control. The 2-year survival rate of the OK-432-injected group was much longer than that of the control. From above results, intralesional injection of immunomodulators was thought to be a promising candidate for the immunotherapy of gastric cancer.

[The tumor--immunological significance of splenectomy for cancer therapy].

In animal experiment, 5 X 10(5) MH-134 tumor cells were transplanted s.c. on the back of the C3H/He mice. Three, seven, 14 and 21 days after tumor transplantation, splenectomy or sham operation were performed and the tumor growth and survival days were examined in each group. As the results, the tumor growth was inhibited and the survival days prolonged not only in the group splenectomized three days but also 21 days after tumor transplantation. Clinically, the effect of splenectomy in combination with immunotherapy on cell-mediated immunity and the survival rates were studied in the gastric cancer patients of upper and middle stomach with 90 cases of stage III and 48 cases at stage IV, totalling 138 cases who underwent total gastrectomy during 1965 and 1981. Immunotherapy was conducted with immunomodulator levamisole at a daily dose of 150 mg, three consecutive days every other week. As a result, splenectomy was not effective for advanced gastric cancer at stage III and in the patients spleen should be retained for immunotherapy. Splenectomy for gastric cancer at stage IV, particularly in combination with immunotherapy, produced augmentation of cell-mediated immunity and longer survival as well. Complications caused by splenectomy were small.