Pharmacological, molecular, and cytogenetic analysis of 'atypical' multidrug-resistant human leukemic cells

W. T. Beck, M. C. Cirtain, M. K. Danks, R. L. Felsted, Ahmad Safa, J. S. Wolverton, D. P. Suttle, J. M. Trent

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

We previously described the cross-resistance patterns and cellular pharmacology of a human leukemic cell line, CEM/VM-1, selected for resistance to the epipodophyllotoxin teniposide (M.K. Danks et al., Cancer Res., 47: 1297-1301, 1987). Compared to CEM/VLB100, which is a well characterized 'classic' multidrug-resistant (MDR) cell line, the CEM/VM-1 cells display 'atypical' multidrug resistance (at-MDR) in that they are cross-resistant to a wide variety of natural product antitumor drugs, except the Vinca alkaloids, and they are not impaired in their ability to accumulate radiolabeled epipodophyllotoxin. We have extended our characterization of this at-MDR cell line in the present study. In comparison to CEM/VLB100 cells, we found that CEM/VM-1 cells are not cross-resistant to either actinomycin D or colchicine. Verapamil and chloroquine, which enhance the cytotoxicity of vinblastine in CEM/VLB100 cells, had little or no ability to do so in the CEM/VM-1 cells. Membrane vesicles of the two resistant sublines were examined for overexpression of the MDR-associated plasma membrane protein (P-glycoprotein, M(r) 170,000 protein, or 180,000 glycoprotein) by photoaffinity labeling with the vinblastine analogue N-(p-azido[3-125I]salicyl)-N'-β-aminoethylvindesine. We were unable to visualize the MDR-associated protein in the CEM/VM-1 membranes with this photoaffinity probe under conditions in which the P-glycoprotein was readily seen in the membranes of CEM/VLB100 cells. Furthermore, no hybridization of the pMDR1 complementary DNA was seen in slot-blot analyses of the RNA from at-MDR cells, indicating that the mdr gene coding for P-glycoprotein is not overexpressed as is the case in the classic MDR cells. However, cytogenetic analysis indicated that the CEM/VM-1 cells contained an abnormally banded region on chromosome 13q, suggesting that a gene other than mdr may be amplified in these cells. Thus, despite the two cell lines having approximately equal degrees of resistance to epipodophyllotoxins, our data indicate that the mechanism(s) responsible for at-MDR is different from that for classic, P-glycoprotein-associated MDR.

Original languageEnglish (US)
Pages (from-to)5455-5460
Number of pages6
JournalCancer Research
Volume47
Issue number20
StatePublished - 1987
Externally publishedYes

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Cytogenetic Analysis
Pharmacology
Multiple Drug Resistance
Podophyllotoxin
Glycoproteins
Cell Line
Vinblastine
Proteins
Membranes
Teniposide
Vinca Alkaloids
Chloroquine
Colchicine
Dactinomycin
Verapamil
Biological Products
Antineoplastic Agents
Genes
Blood Proteins
Complementary DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Beck, W. T., Cirtain, M. C., Danks, M. K., Felsted, R. L., Safa, A., Wolverton, J. S., ... Trent, J. M. (1987). Pharmacological, molecular, and cytogenetic analysis of 'atypical' multidrug-resistant human leukemic cells. Cancer Research, 47(20), 5455-5460.

Pharmacological, molecular, and cytogenetic analysis of 'atypical' multidrug-resistant human leukemic cells. / Beck, W. T.; Cirtain, M. C.; Danks, M. K.; Felsted, R. L.; Safa, Ahmad; Wolverton, J. S.; Suttle, D. P.; Trent, J. M.

In: Cancer Research, Vol. 47, No. 20, 1987, p. 5455-5460.

Research output: Contribution to journalArticle

Beck, WT, Cirtain, MC, Danks, MK, Felsted, RL, Safa, A, Wolverton, JS, Suttle, DP & Trent, JM 1987, 'Pharmacological, molecular, and cytogenetic analysis of 'atypical' multidrug-resistant human leukemic cells', Cancer Research, vol. 47, no. 20, pp. 5455-5460.
Beck WT, Cirtain MC, Danks MK, Felsted RL, Safa A, Wolverton JS et al. Pharmacological, molecular, and cytogenetic analysis of 'atypical' multidrug-resistant human leukemic cells. Cancer Research. 1987;47(20):5455-5460.
Beck, W. T. ; Cirtain, M. C. ; Danks, M. K. ; Felsted, R. L. ; Safa, Ahmad ; Wolverton, J. S. ; Suttle, D. P. ; Trent, J. M. / Pharmacological, molecular, and cytogenetic analysis of 'atypical' multidrug-resistant human leukemic cells. In: Cancer Research. 1987 ; Vol. 47, No. 20. pp. 5455-5460.
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N2 - We previously described the cross-resistance patterns and cellular pharmacology of a human leukemic cell line, CEM/VM-1, selected for resistance to the epipodophyllotoxin teniposide (M.K. Danks et al., Cancer Res., 47: 1297-1301, 1987). Compared to CEM/VLB100, which is a well characterized 'classic' multidrug-resistant (MDR) cell line, the CEM/VM-1 cells display 'atypical' multidrug resistance (at-MDR) in that they are cross-resistant to a wide variety of natural product antitumor drugs, except the Vinca alkaloids, and they are not impaired in their ability to accumulate radiolabeled epipodophyllotoxin. We have extended our characterization of this at-MDR cell line in the present study. In comparison to CEM/VLB100 cells, we found that CEM/VM-1 cells are not cross-resistant to either actinomycin D or colchicine. Verapamil and chloroquine, which enhance the cytotoxicity of vinblastine in CEM/VLB100 cells, had little or no ability to do so in the CEM/VM-1 cells. Membrane vesicles of the two resistant sublines were examined for overexpression of the MDR-associated plasma membrane protein (P-glycoprotein, M(r) 170,000 protein, or 180,000 glycoprotein) by photoaffinity labeling with the vinblastine analogue N-(p-azido[3-125I]salicyl)-N'-β-aminoethylvindesine. We were unable to visualize the MDR-associated protein in the CEM/VM-1 membranes with this photoaffinity probe under conditions in which the P-glycoprotein was readily seen in the membranes of CEM/VLB100 cells. Furthermore, no hybridization of the pMDR1 complementary DNA was seen in slot-blot analyses of the RNA from at-MDR cells, indicating that the mdr gene coding for P-glycoprotein is not overexpressed as is the case in the classic MDR cells. However, cytogenetic analysis indicated that the CEM/VM-1 cells contained an abnormally banded region on chromosome 13q, suggesting that a gene other than mdr may be amplified in these cells. Thus, despite the two cell lines having approximately equal degrees of resistance to epipodophyllotoxins, our data indicate that the mechanism(s) responsible for at-MDR is different from that for classic, P-glycoprotein-associated MDR.

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