The antitumor effect of lowered doses of cytostatics combined with new analogs of vitamin D in mice.

Active and less toxic vitamin D analogs could be useful for clinical applications. In the present study, the antitumor effects of two new synthetic analogs of vitamin D, namely PRI-2202 (24R calcipotriol) and PRI-2205 (5, 6-trans calcipotriol), were evaluated. Since the analogs PRI-2202 and PRI-2205 administered alone inhibited tumor growth only slightly, they were applied in a combined therapy with cytostatics. The in vitro results showed that the synergistic effect between vitamin D analogs and cytostatics was more pronounced when low concentrations of the latter were used. Due to this fact low doses of cytostatics were applied in the in vivo combined treatment schedules. The studies were performed in mouse mammary cancer 4T1 and Lewis lung cancer (LLC) models. Mice bearing subcutaneous tumors were treated with vitamin D analogs and cytostatics in different combinations. Statistically significant inhibition of tumor growth by the combined treatment was observed in 4TI mammary cancer treated with cyclophosphamide and in LLC lung cancer-bearing animals treated with cisplatin. In contrast, no improved therapeutic effect of the combined treatment with low doses of doxorubicin and cyclophosphamide was observed in mice bearing LLC tumors. Moreover, the combined treatment with cisplatin led to increased toxicity, which did not depend on the calcemic activity of the vitamin D analogs. The general conclusion of this work is that combination of vitamin D analogs with cytostatics applied in low doses is not effective in vivo, despite the encouraging in vitro results. Nevertheless, combined treatment with vitamin D analogs was more effective than the treatment with cytostatics applied alone, when higher doses of cytostatics were used.