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The 4-hydroperoxycyclophosphamide (4HC)-resistant B5-1803 subline of the cloned KBM-7/B5 cell line was developed as a model of induced cyclophosphamide resistance in human myeloid leukemia. Based on ICw values, this subline was z20-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 P M 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 B5-1803 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 B5-1803 cells were also cross-resistant to y-radiation ( z 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 eradiction of leukemic cells. Most chronic myeloid leukemia (CML) patients can be rendered disease-free if high-dose cyclophosphamide (Cy