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 cancer cells, we have established a model system in which adriamycin (ADM) induces immediate drug resistance. In this system, human colon carcinoma HT-29 cells were pretreated for 1 h with a subtoxic dose of ADM (0.3 micrograms/ml) and incubated for 24 h in drug-free medium. Then the cells were treated for 1 h with ADM, and the cell survival was determined in terms of colony-forming ability. The survival of the pretreated cells 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 micrograms/ml); more than 99% of the cells were killed. These results indicate that only a small fraction of ADM-pretreated cells acquire the ADM-resistant phenotype. Similar induced resistance was observed in five of seven subclones isolated from HT-29 cells by limiting dilution, suggesting that the majority of cells in the parental HT-29 population could acquire the ADM-resistant phenotype. In the subclone HT-29T9, the ADM pretreatment induced concomitant resistance to daunomycin, VP-16, and VM-26 but not to agents other than topoisomerase II inhibitors. The ADM-induced drug resistance did not accompany MDR1 gene expression and could not be overcome by verapamil, a P-glycoprotein 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.
Tomida
A
A
Institute of Molecular and Cellular Biosciences, University of Tokyo.
Naito
M
M
Tsuruo
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003114:Colony-Forming Units Assay; D004264:DNA Topoisomerases, Type I / Q000032:analysis; D004250:DNA Topoisomerases, Type II / Q000032:analysis; D018076:DNA, Complementary / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000032:analysis; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II