QUALITATIVELY DIFFERENT MECHANISMS OF RESISTANCE TO DOXORUBICIN, BOTHINVOLVING ALTERED GLUTATHIONE POOLS, IN 2 MYELOID CELL-LINES IN-VITRO

Subclones of the two well-characterized myeloid cell lines HL-60 and K G1a were selected for doxorubicin resistance by systematic exposure to increased concentrations of the drug in vitro. Both subclones demonst rated a threefold increased resistance to the drug as evident from cel l growth in liquid culture and clonogenicity ina semisolid matrix. Bot h resistant subclones displayed a similar degree of reduced total and nuclear doxorubicin levels. The HL-60 and the KG1a cells differed qual itatively and quantitatively with respect to glutathione (GSH) levels during culture, with markedly elevated concentrations in the resistant HL-60 subclone during 1 week of culture. Total GSH pools in resistant and sensitive KG1a cells were similar, but maximum GSH levels were re ached earlier in the resistant KG1a clones than in the parental cells. Northern blot analysis suggests that resistance was accompanied by in creased mdr1 expression in the KG1a but not in the HL-60 cells, wherea s alterations in the glutathione S-transferase PI-1 and topoisomerase II message was evident In the latter. The results demonstrate the comp lex, multifactorial mechanisms behind the in vitro induction of even m oderate resistance to anthracyclines.