MECHANISMS OF CYCLOPHOSPHAMIDE RESISTANCE IN A HUMAN MYELOID-LEUKEMIACELL-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 cyc lophosphamide resistance in human myeloid leukemia. Based on IC90 valu es, this subline was approximate to 20-fold resistant to 4HC. Furtherm ore, it was significantly cross-resistant to phosphorodiamidic mustard (PM), whose cytotoxicity is independent of aldehyde dehydrogenase (AD H). Using alkaline elution we found that the resistant line had decrea sed initial levels of DNA interstrand cross-links (ISCs) following 4HC but not PM treatment. The resistant cells also appeared to remove ISC s from their DNA more rapidly than the parental cells. Our data theref ore suggest that 4HC resistance in the B5-180(3) subline is multifacto rial; 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-res istant to gamma-radiation (approximate to 1.7-fold at a surviving frac tion of 0.1); if generally applicable, such effects could have importa nt clinical implications, since pretransplant total body irradiation i s a major component of the eradiction of leukemic cells.