Antitumor and toxic effects of combination chemotherapy with bleomycin and a phenothiazine anticalmodulin agent

Phenothiazines and structurally related calmodulin antagonists acted synergistically with bleomycin in killing malignant cells in culture. For exploration of the potential clinical importance of this observation, the effects of administering the combination of chlorpromazine and bleomycin in vitro and in vivo against the transplantable B16 melanoma were studied. The toxicity of the combination to bone marrow and lungs was also determined. Combined chlorpromazine and bleomycin therapy reduced the concentration of chlorpromazine required to inhibit cellular growth of B16 melanoma cells by greater than half (25 vs. 60 microM). Against the transplanted tumor, after 3 weeks of treatment the tumor sizes (in cubic millimeters) were 540 +/- 100 (vehicle), 520 +/- 120 (chlorpromazine), 170 +/- 10 (bleomycin), and 80 +/- 20 (bleomycin + chlorpromazine, P less than .01 vs. bleomycin alone). The median time required to reach a tumor size of 100 mm3 was 15 days for vehicle and chlorpromazine, 17 days for bleomycin, and 26 days for chlorpromazine and bleomycin together. The doubling time of the tumor was also increased 3.5-fold above control with the two-drug combination. At doses of bleomycin and chlorpromazine that increased antitumor activity, no pulmonary fibrosis, measured histologically and biochemically, was detected. At higher doses of bleomycin, the addition of chlorpromazine diminished lung fibrosis. The combination of drugs was not more toxic to hematopoietic precursors than chlorpromazine alone. These studies suggested that the addition of a phenothiazine to bleomycin can augment the therapeutic efficacy of bleomycin in vivo without substantially increasing its toxicity.