Abstract
We previously reported that some modulators, which enhanced the antitumor activity of doxorubicin, increased the doxorubicin concentration specifically in the tumor. In an attempt to elucidate a part of the mechanism, we compared the membrane transport and the antitumor activity of pirarubicin with those of doxorubicin on M5076 ovarian sarcoma which is known to have low sensitivity to doxorubicin. Pirarubicin uptake by the M5076 showed 2.0 fold of doxorubicin uptake. The 50% cell growth inhibitory concentration and the 50% lethal concentration of pirarubicin were less than those of doxorubicin in vitro. Thus, the cytotoxicity of pirarubicin on M5076 cells was much stronger than that of doxorubicin. It has been suggested that the difference in these cytotoxicities depended on the uptake amounts of antitumor agents by M5076 cells. On M5076 sarcoma bearing mice, doxorubicin did not affect the tumor weight, whereas pirarubicin significantly reduced the tumor weight compared to the control level. Furthermore, pirarubicin prolonged the survival time of M5076 transplanted (iv) mice to 1.5-fold. These in vivo experiments indicated that pirarubicin was more effective on M5076 sarcoma compared to doxorubicin. These results suggested that the increase in the uptake amount of anthracycline in tumor cells might provide the enhancement of antitumor activity.
