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The combined effects of single and fractionated doses of X rays and local heat were investigated using an experimental fibrosarcoma and normal mouse skin. Thermal enhancement ratios were measured from pairs of dose-response curves for both tumour and skin, and the therapeutic advantage of each treatment was then assessed by comparing the enhancement for tumour and skin. For single doses there was a therapeutic advantage when heat was applied three hours after X rays but not with heat applied immediately after irradiation. For two and five daily fractions with heat immediately after irradiation there was significantly less thermal sensitization in tumour than in skin; hence there was a therapeutic loss. When heat was applied at three hours after each fraction there was no thermal sensitization in either skin or tumour; the therapeutic ratio was therefore 1.0. The repair capacity of skin after fractionated X rays alone, or in combination with heat, was also investigated. Heat immediately after X rays caused a small decrease in the repair capacity between two fractions but no decreased repair capacity was observed with five fractions.
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Actual thermal gradients in perfused tissues are difficult to observe using thermocouples because of thermal conduction along the probes. We have used fine type-K (chromel-alumel) probes, which have a much lower thermal conductivity than equivalent-sized type-T (copper-constantan) thermocouples, to examine thermal gradients in two mouse tumour systems during water bath heating. The results indicate substantial heterogeneity in temperature distribution even in tumours transplanted in the foot and immersed to a depth of 2 cm in a 44 degrees C water bath for 20 min, i.e. thermal gradients greater than 1 degree C/mm were observed in KHT fibrosarcomas. The temperature heterogeneity for water bath heating is primarily a result of blood flow and appears to be tumour-specific. Temperature measurements using an excised perfused canine kidney demonstrate that increased perfusate volume flow increases the range of tissue temperatures. Consistent with theory, an artifactual improvement in temperature homogeneity resulted when temperature was measured using type-T thermocouples instead of type-K probes. These results emphasize the difficulties in obtaining accurate temperature measurements during experimental and clinical hyperthermia. Even extensive measurements of temperature in tissues may underestimate the true range of heterogeneity unless factors such as thermal smearing are controlled.
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Delayed-type hypersensitivity (DTH) responses against methylcholanthrene-induced fibrosarcomas in C3H/He and BDF1 mice were developed in BDF1 mice by sc injection of the respective mitomycin C-treated tumor cells. The DTH responses to the allogeneic and the syngeneic tumor cells were accelerated and enhanced tumor-specifically by priming 7 days previously with KCl extracts of the respective tumors. The ability in the mice primed with the tumor extracts enhancing the DTH response against the tumor cells could be transferred to recipient mice by the spleen cells, but not by the T-cell-depleted spleen cells. Rejection of allogeneic tumor was accelerated under the development of accelerated and enhanced DTH response against the allogeneic tumor antigens. Moreover, resistance to syngeneic tumor growth increased significantly with the development of accelerated and enhanced DTH response against the syngeneic tumor antigens. Thus, the augmentation of DTH response by preimmunization with tumor extracts was accompanied by the increased resistance to tumor growth, suggesting that T cells involved in the augmentation of tumor-specific DTH response play some role in increasing the resistance to tumor growth.
This work presents data concerning the effect of tumor excision accompanied or not by the removal of the regional lymph node (RLN) on the survival time of mice bearing the EAkR lymphosarcoma or the B16 melanoma. The operations were performed at various times to study this effect in relation to tumor volume. Early tumorectomy, on day 6 for the EAkR lymphosarcoma, on day 10 for the B16 melanoma, prolonged significantly the survival time. The additional removal of the RLN abolished this beneficial effect. In the case of the EAkR lymphosarcoma, a beneficial effect on the survival time was in contrast observed after a total excision of the tumor accompanied by RLN removal performed on day 8. The two surgical procedures were ineffective in increasing the survival time when they were applied after the 8th day for the EAkR lymphosarcoma and after the 10th day for the B16 melanoma. These results suggest that the preservation of the RLN may be favorable for the host at least at an early stage of the tumor growth.
In allogeneic tumor or skin transplantation, the rejection process that destroys the allogeneic cells leaves syngeneic cells intact by discrimination between self and nonself. Here, we examined whether the cells infiltrating into the allografts could be cytotoxic against syngeneic immortal cells in vitro and in vivo. The leukocytes (i.e., macrophages (Mphi; 55-65% of bulk infiltrates), granulocytes (20-25%), and lymphocytes (15-20%)) infiltrating into allografts, but not into autografts, in C57BL/6 mice were cytotoxic against syngeneic tumor cells and cell lines, whereas the cytotoxic activity was hardly induced in allografted, IFN-gamma-/- C57BL/6 mice. Among the leukocytes, Mphi were the major population of cytotoxic cells; and the cytotoxic activity appeared to be cell-to-cell contact dependent. When syngeneic tumor cells were s.c. injected into normal C57BL/6 mice simultaneously with the Mphi-rich population or allogeneic, but not syngeneic, fibroblastic cells, tumor growth was suppressed in a cell number-dependent manner, and tumor cells were rejected either with a Mphi:tumor ratio of about 30 or with an allograft:tumor ratio of approximately 200. In the case of IFN-gamma-/- C57BL/6 mice, however, the s.c. injection of the allograft simultaneously with tumor cells had no effect on the tumor growth. These results suggest that allograft or allograft-induced Mphi may be applicable for use in cancer treatment and that IFN-gamma induction by the allograft may be crucial for the treatment.
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