This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Long, B. H. Articles by Casazza, A. M. Search for Related Content PubMed PubMed Citation Articles by Long, B. H. Articles by Casazza, A. M.

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.

This article has been cited by other articles:

				L. Vahdat Ixabepilone: A Novel Antineoplastic Agent with Low Susceptibility to Multiple Tumor Resistance Mechanisms Oncologist, March 1, 2008; 13(3): 214 - 221. [Abstract] [Full Text] [PDF]

				W. C. Rose, F. Y. F. Lee, C. R. Fairchild, M. Lynch, T. Monticello, R. A. Kramer, and V. Manne Preclinical Antitumor Activity of BMS-214662, a Highly Apoptotic and Novel Farnesyltransferase Inhibitor Cancer Res., October 1, 2001; 61(20): 7507 - 7517. [Abstract] [Full Text] [PDF]

				W. C. Rose, B. H. Long, C. R. Fairchild, F. Y. F. Lee, and J. F. Kadow Preclinical Pharmacology of BMS-275183, an Orally Active Taxane Clin. Cancer Res., July 1, 2001; 7(7): 2016 - 2021. [Abstract] [Full Text] [PDF]

				F. Y. F. Lee, R. Borzilleri, C. R. Fairchild, S.-H. Kim, B. H. Long, C. Reventos-Suarez, G. D. Vite, W. C. Rose, and R. A. Kramer BMS-247550: A Novel Epothilone Analog with a Mode of Action Similar to Paclitaxel but Possessing Superior Antitumor Efficacy Clin. Cancer Res., May 1, 2001; 7(5): 1429 - 1437. [Abstract] [Full Text]

				F. Errington, E. Willmore, M. J. Tilby, L. Li, G. Li, W. Li, B. C. Baguley, and C. A. Austin Murine Transgenic Cells Lacking DNA Topoisomerase IIbeta Are Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and Cleavable Complex Formation Mol. Pharmacol., December 1, 1999; 56(6): 1309 - 1316. [Abstract] [Full Text]

				E. Willmore, A. J. Frank, K. Padget, M. J. Tilby, and C. A. Austin Etoposide Targets Topoisomerase IIalpha and IIbeta in Leukemic Cells: Isoform-Specific Cleavable Complexes Visualized and Quantified In Situ by a Novel Immunofluorescence Technique Mol. Pharmacol., July 1, 1998; 54(1): 78 - 85. [Abstract] [Full Text]