Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas

Susan E. Bates, Ching Yi Shieh, Lyn A. Mickley, Helén L. Dichek, Adi Gazdar, D. Lynn Loriaux, Antonio Tito Fojo

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

P-Glycoprotein (Pgp), product of the mdr-1 gene, is a 130- to 180-kDa plasma membrane phosphoglycoprotein which mediates multidrug resistance in cell culture by increasing efflux of the natural product chemotherapeutic agents. High levels of expression of mdr-1/Pgp are found in both the normal adrenal and adrenocortical cancers. By RNA in situ hybridization the expression in adrenocortical cancer is shown to be widely distributed. The present study demonstrates that decreased drug accumulation mediated by mdr-1/Pgp can be overcome by clinically achieveable concentrations of mitotane (o,p′-DDD). The increase in drug accumulation with the addition of mitotane is due at least in part to a decrease in drug efflux and results in an increase in cytotoxicity when agents of the natural product class are used. This effect is observed in cells with a broad range of mdr-1/Pgp expression, including levels comparable to those found in most adrenocortical cancers. Similar increases in drug accumulation can be demonstrated in an unselected adrenocortical cancer cell line that expresses mdr-1/Pgp. The finding that multidrug resistance mediated by mdr-1/Pgp can be reversed by mitotane provides a rational basis for exploring the use of mitotane in combination with natural product chemotherapeutic agents in adrenocortical cancer.

Original languageEnglish (US)
Pages (from-to)18-29
Number of pages12
JournalJournal of Clinical Endocrinology and Metabolism
Volume73
Issue number1
StatePublished - Jul 1991

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Adrenal Cortex Neoplasms
Mitotane
Adrenocortical Carcinoma
MDR Genes
Chemotherapy
Cytotoxicity
Genes
Cells
Drug Therapy
Cell Line
Biological Products
Multiple Drug Resistance
Pharmaceutical Preparations
Adrenal Gland Neoplasms
P-Glycoprotein
Cell membranes
Cell culture
In Situ Hybridization
Cell Culture Techniques
Cell Membrane

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas. / Bates, Susan E.; Shieh, Ching Yi; Mickley, Lyn A.; Dichek, Helén L.; Gazdar, Adi; Loriaux, D. Lynn; Fojo, Antonio Tito.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 73, No. 1, 07.1991, p. 18-29.

Research output: Contribution to journalArticle

Bates, Susan E. ; Shieh, Ching Yi ; Mickley, Lyn A. ; Dichek, Helén L. ; Gazdar, Adi ; Loriaux, D. Lynn ; Fojo, Antonio Tito. / Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas. In: Journal of Clinical Endocrinology and Metabolism. 1991 ; Vol. 73, No. 1. pp. 18-29.
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