Antitumor effects of ketoconazole and trifluoperazine in murine T-cell lymphomas

In vitro and in vivo antitumor effects of ketoconazole (KTZ), trifluoperazine (TFP), and combinations of both drugs were examined in cell lines established from radiation leukemia virus (RadLV)-induced T-cell lymphomas. KTZ inhibited [3H]-thymidine incorporation in the tumor cells in vitro; 50% inhibition of DNA synthesis was observed at concentrations of 4-7 micrograms/ml. [3H]-thymidine uptake in bone-marrow and spleen cells prepared from healthy mice was also inhibited by KTZ, but 50% inhibition was observed only at a concentration of 50 micrograms/ml. Stimulation of spleen cells with concanavalin A led to an increase in their sensitivity to the inhibition of DNA synthesis by KTZ. The tumor-cell lines varied in their sensitivity to the inhibition of DNA synthesis by TFP, and the effects of TFP on DNA synthesis in bone-marrow and spleen cells were similar to those observed in the tumor cells. Synergistic, additive, or less than additive effects of the drug combinations on the inhibition of DNA synthesis in vitro were observed both in tumor cells and in bone-marrow cells. In vivo experiments were conducted on groups of C57BL/6 (B6) mice that were inoculated s.c. with tumor cells and then treated with i.p. injections of KTZ, TFP or both. Control groups were injected with phosphate-buffered saline (PBS). Each of the drugs alone as well as their combinations caused a significant delay in the appearance of palpable tumors, a decrease in tumor size, and a marked prolongation of survival. The concentrations of the drugs used in in vivo experiments did not affect the WBC counts in the peripheral blood of healthy mice. KTZ is currently used for the treatment of prostatic cancer because of its inhibitory effect on testosterone biosynthesis. The results of the present study indicate the hormone-independent chemotherapeutic potential of KTZ, TFP, and combinations of the two drugs.