Increased effects of MPDAX, a novel xanthine derivative, on antitumor activity of doxorubicin.

To clarify the effect of 1-methyl-3-propyl-7-N,N-dimethylpropylamide-xanthine (MPDAX) on doxorubicin (DOX) transport, we examined the efficacy of MPDAX as an amplifier of the antitumor activity of DOX in mice bearing tumors with different properties as to DOX transport across cell membranes. MPDAX significantly enhanced the DOX-induced antitumor activity on DOX-sensitive tumors. It is expected that the increase in antitumor activity caused by MPDAX contributes to the increased DOX concentration in tumors due to the MPDAX-induced change in DOX transport via the transporter expressed in sensitive tumor cells. In contrast, in M5076, a lower sensitive to DOX, MPDAX decreased the tumor weight by half at an otherwise ineffective dose of DOX. Furthermore, in P388/DOX, DOX has no effect, but MPDAX caused an elevation of the DOX-induced antitumor activity with an increase in the DOX concentration in the tumors. The results suggested that MPDAX is a novel amplifier for antitumor agents as it significantly increased the antitumor activity toward tumors with different properties. The DOX concentrations in the MPDAX + DOX group for all tumor lines were about two-fold those in the DOX alone group. Furthermore, MPDAX and DOX exhibited significant inhibitory effects on uridine and thymidine uptake. It is known that nucleoside transporters increase the membrane permeability of DOX. We speculated that MPDAX inhibits the cell membrane transport of uridine and thymidine via nucleoside transporters. MPDAX, acting via nucleoside transporters, increases the DOX-induced antitumor activity toward many tumor types and is an useful biochemical modulator.