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Mechanisms of cyclophosphamide resistance in a human myeloid leukemia cell line.

The 4-hydroperoxycyclophosphamide (4HC)-resistant B5-180(3) subline of the cloned KBM-7/B5 cell line was developed as a model of induced cyclophosphamide resistance in human myeloid leukemia. Based on IC90 values, this subline was approximately 20-fold resistant to 4HC. Furthermore, it was significantly cross-resistant to phosphorodiamidic mustard (PM), whose cytotoxicity is independent of aldehyde dehydrogenase (ADH). Using alkaline elution we found that the resistant line had decreased initial levels of DNA interstrand cross-links (ISCs) following 4HC but not PM treatment. The resistant cells also appeared to remove ISCs from their DNA more rapidly than the parental cells. Our data therefore suggest that 4HC resistance in the B5-180(3) subline is multifactorial; ADH is an important mediator of its resistance to ISC induction by 4HC, while a second process, which may involve an increased ability to tolerate drug-induced DNA damage, appears to be important for its resistance to both 4HC and PM. The B5-180(3) cells were also cross-resistant to gamma-radiation (approximately 1.7-fold at a surviving fraction of 0.1); if generally applicable, such effects could have important clinical implications, since pretransplant total body irradiation is a major component of the eradication of leukemic cells.