EFFECTS OF SYSTEMICALLY ADMINISTERED BLEOMYCIN OR ADRIAMYCIN WITH LOCAL HYPERTHERMIA ON PRIMARY TUMOR AND LUNG METASTASES

Abstract

Exposure of cells in tissue culture to bleomycin or adriamycin during 43.degree. C hyperthermia increased cytotoxicity dramatically compared to exposure at 37.degree. C. This study was designed to test whether this interaction was useful in tumor-bearing animals. C3H mice bearing the KHT tumor [mammary carcinoma] were treated with bleomycin (7 or 15 mg/kg) or with adriamycin (2.5 or 5 mg/kg) with or without local heating of the tumor to 43.degree. C for 30 min by 13.56 MHz radiofrequency fields. The effects were assessed by growth delay (mean tumor diameter doubling time) and cure rate. In separate experiments, BALB/c mice bearing EMT6 [mammary carcinoma] tumors were treated identically, but tumors were excised 2 h after treatment and tumor cell survival was assayed by colony formation. Antitumor effects of systemic bleomycin were potentiated by local hyperthermia. The 2 modalities had to be administered close together in time to observe the potentiation, suggesting a true interaction. There was a threshold for bleomycin potentiation in vivo between 42.degree. C and 43.degree. C, just as observed in tissue culture experiments. The antitumor activity of adriamycin was not potentiated in vivo in these tumor systems except in cell survival experiments at doses higher than those compatible with survival of the host. The toxicity of drug combined with heat was greater than that of either modality alone. Hyperthermia did not adversely affect the incidence or severity of spontaneous lung metastases from KHT tumors. In fact, groups treated with heat and bleomycin had less severe lung metastases than groups treated with bleomycin alone. Local heating of tumors may be useful adjunct to systemic bleomycin therapy. In vivo potentiation of adriamycin by heat could not be demonstrated in these tumor systems.