Characteristics of P388/VMDRC.04, a Simple, Sensitive Model for Studying P-Glycoprotein Antagonists

Jin Ming Yang, Sarah Goldenberg, Michael M. Gottesman, William N. Hait

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Cross-resistance to chemotherapeutic drugs is a significant problem in the treatment of patients with cancer. The discovery that this phenomenon is associated with the overexpression of a membrane glycoprotein, P-glycoprotein, which acts as a drug efflux pump, has provided a new target for drug development. To develop a model for identifying new compounds which can block the function of P-glycoprotein, we infected P388 mouse leukemic cells with a retrovirus containing a cloned human MDR1 complementary DNA The new cell line, P388/VMDRC.04, incorporated and overexpressed the human gene as evidenced by Southern blots, increased mRNA and protein synthesis, and recognition by the MRK16 monoclonal antibody. P388/VMDRC.04 was cross-resistant to colchicine, vincristine, and doxorubicin, and the degree of resistance correlated with a reduction in cellular drug accumulation. Unlike many cell lines selected for resistance by growth in increasing concentrations of drug for prolonged periods of time, these cells did not show alternative mechanisms of resistance such as increased synthesis of glutathione or alterations in topoisomerase II. In addition, the sensitivity of P388/VMDRC.04 cells was completely restored by cyclosporin A and trans-flupenthixol. P388/VMDRC.04 cells were subcloned and 10 clones were picked for in vivo evaluation. One subclone grew similarly to parental cells in female BALB/c × DBA/2 F1 mice and showed no responsiveness to therapeutic doses of vincristine or etoposide. The combination of vincristine with cyclosporin A significantly increased the survival of mice inoculated with P388/VMDRC.04 cells. The availability of a cell line that displays the MDR phenotype, overexpresses human P-glycoprotein, but does not contain alterations in at least two well-defined alternative mechanisms of resistance, and that can be grown in simple animal models should facilitate the development of new agents active against this form of chemotherapeutic drug resistance.

Original languageEnglish (US)
Pages (from-to)730-737
Number of pages8
JournalCancer Research
Volume54
Issue number3
StatePublished - Feb 1994

Fingerprint

P-Glycoprotein
Vincristine
Pharmaceutical Preparations
Cell Line
Cyclosporine
Flupenthixol
Type II DNA Topoisomerase
Membrane Glycoproteins
Colchicine
Etoposide
Retroviridae
Southern Blotting
Drug Resistance
Doxorubicin
Glutathione
Animal Models
Complementary DNA
Clone Cells
Monoclonal Antibodies
Phenotype

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yang, J. M., Goldenberg, S., Gottesman, M. M., & Hait, W. N. (1994). Characteristics of P388/VMDRC.04, a Simple, Sensitive Model for Studying P-Glycoprotein Antagonists. Cancer Research, 54(3), 730-737.
Yang, Jin Ming ; Goldenberg, Sarah ; Gottesman, Michael M. ; Hait, William N. / Characteristics of P388/VMDRC.04, a Simple, Sensitive Model for Studying P-Glycoprotein Antagonists. In: Cancer Research. 1994 ; Vol. 54, No. 3. pp. 730-737.
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Yang, JM, Goldenberg, S, Gottesman, MM & Hait, WN 1994, 'Characteristics of P388/VMDRC.04, a Simple, Sensitive Model for Studying P-Glycoprotein Antagonists', Cancer Research, vol. 54, no. 3, pp. 730-737.

Characteristics of P388/VMDRC.04, a Simple, Sensitive Model for Studying P-Glycoprotein Antagonists. / Yang, Jin Ming; Goldenberg, Sarah; Gottesman, Michael M.; Hait, William N.

In: Cancer Research, Vol. 54, No. 3, 02.1994, p. 730-737.

Research output: Contribution to journalArticle

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