COMBINED ORAL-ADMINISTRATION OF ETOPOSIDE AND ARABINOFURANOSYLCYTOSINE-5'-STEARYLPHOSPHATE ENHANCES THE ANTITUMOR EFFECT AGAINST P388 ASCITES TUMORS

We investigated the antitumor effect of oral administration of etoposi de and arabinofuranosylcytosine-5'-stearylphosphate (C18PCA) against P 388 ascites tumors in B6D2F1 mice. Etoposide (25 mg/kg) and C18PCA (5 mg/kg) were given orally on days 1-5 after tumor inoculation. The medi an life span of the mice treated with etoposide or C18PCA alone was 19 .5 and 18 days, respectively. The combination of both drugs significan tly extended the median life span to 33 days. To clarify this enhancem ent of the increase in median life span, we examined intracellular deo xyribonucleoside triphosphate (dNTP) pools, cell-cycle distribution, D NA fragmentation, and the time course of the plasma drug concentration . Etoposide had no effect on intracellular dNTP pools in this experime ntal system, whereas treatment of cells with C18PCA or with the combin ation of both drugs resulted in a significant increase in dTTP pools t o values ranging from 1.8- to 2.0-fold higher than the control levels. There was a significant increase in cells in the S+G2/M phase when ce lls had been treated with both etoposide and C18PCA. Agarose-gel elect rophoresis of the extracted DNA revealed that C18PCA enhanced the frag mentation of DNA, with a length of about 180 bp being induced by etopo side. The plasma peak levels of etoposide (1000 nM) and ara-C (50 nM) were observed at 20 and 30 min after the simultaneous administration o f both drugs, respectively. The plasma etoposide level gradually decre ased to 10% of the peak level at 240 min after administration. On the other hand, the plasma concentration of ara-C was maintained at above 20 nM at 240 min. These observations suggest that C18PCA and etoposide act on P388 murine leukemic cells by accumulating cells in the S+G2/M phase. Even if the plasma concentration of ara-C is low, the repair o f DNA damage by etoposide may be hindered in the presence of ara-C fol lowing an increase in DNA fragmentation.