Effect of methylxanthine derivatives on doxorubicin transport and antitumor activity

Biochemical modulation, which is more effective with the use of antitumor agents, has recently played very important role in cancer chemotherapy. In this review, it was reported that some of the methylxanthine derivatives, e.g. caffeine, were useful for modulator and attempted to defined the relation between the effect of methylxanthine derivatives on the doxorubicin transport and antitumor activity. Caffeine and theobromine inhibited the doxorubicin efflux from tumor cells, increased the doxorubicin concentration in a tumor, and enhanced the antitumor effect of doxorubicin. However, the caffeine metabolites, which had no effect on the doxorubicin efflux, did not increase antitumor activity. Moreover, caffeine and theobromine did not enhance the side toxicity of doxorubicin on the lipid peroxide level, DNA biosynthesis and the doxorubicin concentrations in normal tissues. Moreover, we investigated the effect of the combination of doxorubicin with caffeine or theobromine on the change in cyclic adenosine 3',5'-monophosphate (cyclic AMP) in tissues in vivo, and the effect of cyclic AMP on doxorubicin efflux in vitro, and measured the distribution of caffeine and theobromine in normal and tumor tissues. In Ehrlich ascites carcinoma bearing mice, the level of cyclic AMP in a tumor was decreased by doxorubicin. With the combination of caffeine or theobromine and doxorubicin, the cyclic AMP level recovered to the control level. This tendency was not seen in normal tissues (heart and liver). Moreover, the doxorubicin efflux from the Ehrlich cells was inhibited on the addition of cyclic AMP in vitro. And the caffeine concentration in the tumors was the same as that in the heart, and was increased in combination with doxorubicin compared with that in the caffeine-only group during the 4 hr after caffeine treatment. Furthermore, the doxorubicin efflux was promoted by the supply of energy (addition of glucose), influx was decreased relatively, doxorubicin efflux needs the existence of glucose and the inhibition of energy related drug export pump by caffeine induced inhibition of doxorubicin efflux. The treatment of doxorubicin nor caffeine, and any treatment schedule did not change the amount and appearance of GLUT 1 as glucose transporter on Ehrlich ascites carcinoma cell. For the mentioned above, we thought as concerns the increase of antitumor activity of doxorubicin by caffeine which is xanthine derivatives as follows. Caffeine distributes, high level in tumor, keeps the cyclic AMP level, and effects glucose transport or doxorubicin transport depend on energy and inhibits doxorubicin efflux. And then DNA synthesis was increased with the maintenance the concentration of doxorubicin in tumor. These action did not show in normal tissues, caffeine did not influence the side toxicity of doxorubicin. These results suggested that caffeine which is one of xanthine derivatives will be useful for biochemical modulator.