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Mechanisms of Resistance to Etoposide and Teniposide in Acquired Resistant Human Colon and Lung Carcinoma Cell Lines¹

Departments of Experimental Therapeutics [B. H. L., A. L., R. C. C. W., A. M. C.], Cellular and Molecular Biology [L. W.], Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol-Meyers Squibb Company, Wallingford, Connecticut 06492, and Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [M. G. B.]

Stable acquired resistance to etoposide (VP-16) or teniposide (VM-26) in HCT116 human colon carcinoma cells and A549 human lung adenocarcinoma cells, was previously obtained by weekly 1-h exposures to either drug (B. H. Long, Natl. Cancer Inst. Monogr., 4: 123–127, 1987). The purpose of this study was to identify possible mechanisms of resistance present in these cells by using human mdr1 and topoisomerase II DNA probes, antibodies to these gene products, and P4 phage unknotting assay for topoisomerase II activities. HCT116(VP)35 cells were 9-, 7-, and 6-fold resistant to VP-16, VM-26, and Adriamycin, respectively, and showed no cross-resistance to colchicine and actinomycin D. These cells had no differences in mdr1 gene, mdr1 mRNA, or P-glycoprotein levels but displayed decreased levels of topoisomerase II mRNA and enzyme activity without any alteration of drug sensitivity displayed by the enzyme. HCT116(VM)34 cells were 5-, 7-, and 21-fold resistant to VP-16, VM-26, and Adriamycin; were cross-resistant to colchicine (7-fold) and actinomycin D (18-fold); and possessed a 9-fold increase in mdr1 mRNA and increased P-glycoprotein without evidence of mdr1 gene amplification. No alterations in topoisomerase II gene or mRNA levels, enzyme activity, or drug sensitivity were observed. A549(VP)28 and A549(VM)28 cells were 8-fold resistant to VP-16 and VM-26 and 3-fold resistant to Adriamycin. Both lines were not cross-resistant to colchicine or actinomycin D but were hypersensitive to cis-platinum. No alterations in mdr1 gene, mdr1 mRNA, or P-glycoprotein levels, but lower topoisomerase II mRNA levels and decreased enzyme activities, were observed. Of the four acquired resistant cell lines, resistance is likely related to elevated mdr1 expression in one line and to decreased topoisomerase II expression in the other three lines.

¹ Portions of the research presented in this publication were supported by a grant from the USPHS, National Cancer Institute, Grant CA-40449.

² To whom requests for reprints should be addressed.

³ Present address: C.R.O., Via Pedemontana Occ., 22081 Aviano (PN), Italy.

Received 1/31/90. Accepted 7/17/91.

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