Enhanced efficacy of 1-methyl-3-propyl-7-butylxanthine on the antitumor activity of doxorubicin against doxorubicin-resistant P388 leukemia

The effects of 1-methyl-3-propyl-7-butylxanthine (MPBX), a xanthine derivative, on doxorubicin (DOX)-induced antitumor activity against DOX-sensitive P388 leukemia (P388) and DOX-resistant P388 leukemia (P388/DOX) have been examined. In P388-bearing mice, the combination of MPBX with DOX increased the antitumor activity of DOX 1.6-fold. In contrast, in P388/DOX-bearing mice, DOX alone did not decrease the tumor weight, whereas in combination with MPBX it significantly decreased the tumor weight in the control group by 50%. The increase in DOX-induced antitumor activity caused by MPBX was correlated with the DOX concentration in the tumors. The DOX concentration in the tumors of P388- and P388/DOX-bearing mice in the MPBX combination group increased by 1.3-fold and 2.2-fold, respectively, compared to the level in the DOX-alone group. On the other hand, there was no increase in the DOX concentration in the heart or liver in both types of tumor-bearing mice treated with MPBX. In vitro, the facilitated DOX influx and suppressed efflux by MPBX in both types of tumor cells were similar, suggesting that MPBX acts on the same site in both types of cells. P388/DOX overexpressed P-glycoprotein, i.e. the inhibitory order of DOX efflux caused by the inhibitor of P-glycoprotein was P388 < P388/DOX. However, the effect of MPBX was P388 > P388/DOX. Therefore, we expect that the site of attack by MPBX is not P-glycoprotein.