ACQUISITION OF DOXORUBICIN RESISTANCE IN HUMAN LEUKEMIA HL-60 CELLS IS REPRODUCIBLY ASSOCIATED WITH 7Q21 CHROMOSOMAL-ANOMALIES

Tumor cell resistance to doxorubicin (DOX(3)) is usually associated wi th the overexpression of P-glycoprotein (PGP) in model systems. We hav e characterized the karyotypic changes in two sublines of HL-60 cells which differ in the induction of differentiation by retinoic acid. The parental sublines, designated HL-60A/S and HL-60Y/S, were selected in increasing concentrations of 0.025-0.1: mu g/mL DOX. Monosomy 8 in HL -60Y/S was the only karyotypic difference prior to DOX exposure, Both sublines acquired 7q+ markers upon exposure to DOX. In HL-60Y/S, an ad d(7)(q21) replaced one homologue at 0.025 mu g/mL DOX, and an add(7)(q 32) appeared which replaced the other normal 7 at 0.05 mu g/mL DOX. Th e HL-60A/S cells acquired an add(7)(q21) at 0.025 mu g/mL DOS. The 7q abnormalities involved breakpoints in the midregion of 7q. The overex pression of phosphorylated PGP in immunoprecipitates with C-219 antibo dy was identified in both sublines of DOX-resistant HL-60 cells with 7 q+ abnormalities, and this is consistent with the location of mdr-1 se quences to 7q21-21.1. Also, analysis of RNA from parental-sensitive an d DOX-resistant sublines by reverse transcriptase;polymerase chain rea ction revealed: a) comparable expression of multidrug resistance relat ed protein (MRP) in sensitive and resistant sublines; and b) overexpre ssion of mdr-1 only in the DOX-resistant sublines, Thus, the selection of DOX resistance in two sublines of NL-60 cells which differ in thei r response to retinoic-acid-induced myeloid differentiation is reprodu cibly associated with overexpression of mdr-1 versus MRP.