ACUTE INDUCTION OF ADRIAMYCIN-RESISTANCE IN HUMAN COLON-CARCINOMA HT-29 CELLS EXPOSED TO A SUBLETHAL DOSE OF ADRIAMYCIN

To study the mechanisms of the acute induction of drug resistance in c ancer cells, we have established a model system in which adriamycin (A DM) induces immediate drug resistance. In this system, human colon car cinoma HT-29 cells were pretreated for 1 h with a subtoxic dose of ADM (0.3 mu g/ml) and incubated for 24 h in drug-free medium. Then the ce lls were treated for 1 h with ADM, and the cell survival was determine d in terms of colony-forming ability. The survival of the pretreated c ells was increased up to 100-fold, as compared with that of untreated cells. Such increased survival, however, was observed only after high doses of ADM (2 to 8 mu g/ml); more than 99% of the cells were killed. These results indicate that only a small fraction of ADM-pretreated c ells acquire the ADM-resistant phenotype. Similar induced resistance w as observed in five of seven subclones isolated from HT-29 cells by li miting dilution, suggesting that the majority of cells in the parental HT-29 population could acquire the ADM-resistant phenotype. In the su bclone HT-29T9, the ADM pretreatment induced concomitant resistance to daunomycin, VP-16, and VM-26 but not to agents other than topoisomera se II inhibitors. The ADM-induced drug resistance did not accompany MD R1 gene expression and could not be overcome by verapamil, a P-glycopr otein inhibitor. The present system could be useful to study the acute induction mechanism(s) of ADM-resistance, which could be relevant to clinical resistance in patients.