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 multidrug-resistant tumors, by inhibiting P-glycoprotein function, and increase the anti-cancer drug efficacy against drug-sensitive tumors, by increasing doxorubicin bioavailability. Since the success of such combined chemotherapy treatments might have been limited by the myelotoxicity 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 lymphohaematopoietic grafts from the donor mice. Analyzed parameters were blood, lymphoid and myeloid cell numbers, proliferative responses to T- and B-cell mitogens, and serum immunoglobulin levels. Cell alterations caused by doxorubicin alone were potentiated by SDZ PSC 833, but did not persist in scid recipients. Chemotherapy regimens combining SDZ PSC 833 and doxorubicin, and known for their therapeutic benefit for multidrug-resistant tumor-bearing mice, only caused a rather mild toxicity for the lympho-myeloid system of normal mice.
Pourtier-Manzanedo
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Laboratoire d'Immunologie-II, Faculté de Pharmacie, Université Louis Pasteur, Strasbourg, France.
Didier
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Froidevaux
S
S
Loor
F
F
D000818:Animals; D003524:Cyclosporins / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007107:Immune System / Q000187:drug effects; D007132:Immunoglobulin Isotypes / Q000097:blood; D008208:Lymphatic System / Q000166:cytology / Q000187:drug effects*; D051379:Mice
D003524:Cyclosporins; D007132:Immunoglobulin Isotypes; D004317:Doxorubicin; C070272:valspodar