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-1(+) 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 a 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. (C) 1994 Wiley-Liss, Inc.