Myeloid and lymphoid cell alterations in normal mice exposed to chemotherapy with doxorubicin and/or the multidrug-resistance reversing agent SDZ PSC 833.
The cyclosporin SDZ PSC 833 (PSC) is a potent in vivo chemosensitizer for tumor cells with P-glycoprotein(Pgp)-dependent multidrug resistance (MDR). However, Pgp expression also occurs in CD8+ T cells, NK cells, macrophages and stem cells. In order to find whether PSC might display specific myelotoxicity or potentiate the toxicity of anti-cancer drugs, healthy mice were exposed to single doxorubicin (DOX) and combined (DOX + PSC) chemotherapy protocols known to be near or above the borderline of toxicity for tumor-bearing mice. Mice treated with DOX alone or with (DOX + PSC) showed transient spleen hypoplasia, with a general decrease of all leucocyte lineages and a persistent fall in the numbers of B cells in the bone marrow. In (DOX + PSC)-treated mice, PSC only potentiated the DOX effects without inducing specific depletions of the Pgp-expressing leukocytes (CD8+ and Mac-I+ cells). Hematopoietic cell grafts from normal mice to (DOX +/- PSC)-treated mice did not correct their B-cell lineage deficiency. When lethally irradiated mice were rehabilitated with hematopoietic cells from (DOX +/- PSC)-treated mice (including those with very reduced survival), all chimeras survived for at least 8 months after the cell graft, at which time their leucocyte population profiles were similar to those of control chimeras.
Froidevaux
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S
Pre-clinical Research Department, Sandoz Pharma Ltd., Basel, Switzerland.
Loor
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F
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D007958:Leukocyte Count; D008214:Lymphocytes / Q000187:drug effects*; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
D003524:Cyclosporins; D004317:Doxorubicin; C070272:valspodar