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The combined effects of water-bath hyperthermia at 42.5 degrees C for 30 min, 1/10 LD50 Bleomycin iv, and 200 rad x irradiation were studied in DDD strain male mice with Ehrlich ascites tumor. The objective was to acquire data on the optimum regimen for a combined administration of these three modalities. The treatments were given 10 days after the inoculation of 2 X 10(6) of the cells into the right hind limb. Concomitant application of the three modalities led to an 80% regression. A single modality produced no significant effect and a 30-50% regression occurred when only two modalities were combined. To assess the influence of timing and sequence, hyperthermia was applied at 1, 2, 4, and 6 hr before, after, or simultaneously with the combination of Bleomycin and 200 rad X ray. A significant effect was obtained in the case of concomitant application of the three and hyperthermia was effective when applied within 2 hr before or after administration of Bleomycin plus irradiation. This enhancement disappeared at 4-hr intervals.

The therapeutic effects of combined treatment with hyperthermia (HT) and temperature-sensitive liposomes (TSL) containing Bleomycin (BLM) were evaluated in metastatic lymph nodes of AH-66 ascites tumor in rats. As a model for metastatic lymph nodes, 4 X 10(6) cells of AH-66 were inoculated into the right popliteal lymph nodes of rats. Seven days after inoculation, when the tumor in popliteal lymph nodes was approximately 8 mm in diameter, TSL-BLM was injected subcutaneously into the right foot pad, and local hyperthermia at 43 degrees C was applied for 20 minutes. The most obvious suppression of tumor growth and excellent survival rate were obtained in rats which received both TSL-BLM and HT, compared with groups receiving HT or TSL-BLM alone. These findings suggest that the combination of TSL-BLM and HT provides an effective cancer chemotherapy for patients with metastatic lymph nodes.

The effects of 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br cGMP) on intracellular free calcium concentrations ([Ca2+]i) in cultured rat aortic vascular smooth muscle cells (VSMCs) loaded with fura-2 were recorded microfluorometrically. Irrespective of whether VSMCs were at rest (in 5 mM K+ PSS), under Ca2+ depletion (in Ca2+-free medium for 10 min) and K+ depolarization (in high K+ PSS), [Ca2+]i was actively reduced and reached a new and lower steady-state level with the application of 8-Br cGMP. This may be the first and direct evidence that cGMP, a putative mediator of various vasodilators, actively reduces [Ca2+]i in VSMCs.