Inhibition of DNA biosynthesis by vincristine and pentoxifylline in murine P388 leukemia cells resistant to doxorubicin

Pentoxifylline (PTX) is a methylxanthine used clinically in the treatment of intermittent claudication. It is an active hemorheological agent used for the treatment of defective microcirculation. The use of the anticancer agent vincristine is limited by its toxicity to normal body tissues. The data presented in the present paper show that it is possible to achieve greater cell-kill by using vincristine in combination with pentoxifylline. The effect of pentoxifylline alone and in combination with vincristine was studied using membrane filtration technique in P388 leukemia (P388) and its subline P388/DOX resistant to doxorubicin and cross-resistant to vincristine. Pentoxifylline (100 mumol/l) had minimal inhibitory effect on DNA biosynthesis in P388 leukemia cells. Vincristine, at the concentration employed in this study did not show significant inhibition of DNA biosynthesis confirming multidrug resistant nature of P388/DOX cells. Pentoxifylline had a dose-sparing effect, wherein it enhanced the antiproliferative activity of vincristine at a clinically achievable concentration. The studies on reversibility of inhibition of DNA biosynthesis in P388/DOX cells pretreated with vincristine and pentoxifylline showed the irreversible nature of the effect of combination of vincristine and pentoxifylline. This observation warrants the possible use of pentoxifylline as an adjuvant in cancer chemotherapy.