LYMPHOTOXICITY AND MYELOTOXICITY OF DOXORUBICIN AND SDZ PSC-833 COMBINED CHEMOTHERAPIES FOR NORMAL MICE

In the mouse, the P-glycoprotein-directed chemosensitizer SDZ PSC 833 could both restore a therapeutic window for doxorubicin against multid rug-resistant tumors, by inhibiting P-glycoprotein function, and incre ase the anti-cancer drug efficacy against drug-sensitive tumors, by in creasing doxorubicin bioavailability. Since the success of such combin ed chemotherapy treatments might have been limited by the myelotoxicit y of doxorubicin and the P-glycoprotein expression on some blood cells , their lymphotoxicity and myelotoxicity was studied on normal B6D2F1 mice, and whenever possible, the persistence of blood cell alterations was also searched for in scid recipients of lympho-haematopoietic gra fts from the donor mice. Analyzed parameters were blood, lymphoid and myeloid cell numbers, proliferative responses to T- and B-cell mitogen s, and serum immunoglobulin levels. Cell alterations caused by doxorub icin alone were potentiated by SDZ PSC 833, but did not persist in sci d recipients. Chemotherapy regimens combining SDZ PSC 833 and doxorubi cin, and known for their therapeutic benefit for multidrug-resistant t umor-bearing mice, only caused a rather mild toxicity for the lympho-m yeloid system of normal mice.