Myeloid and lymphoid cell alterations in normal mice exposed to chemotherapy with doxorubicin and/or the multidrug‐resistance reversing agent SDZ PSC 833

Publisher Website
Google Scholar
Abstract
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‐l+ 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.