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Transient Induction of the MRP/GS-X Pump and -Glutamylcysteine Synthetase by 1-(4-Amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea in Human Glioma Cells¹

Department of Molecular Pathology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [A. G., M. T. K.]; Department of Surgical Neurology, Jichi Medical School, Minamikawachi, Tochigi 329-04, Japan [A. G., S. S., T. M.]; and Department of Medicinal Biology, Central Research, Pfizer, Inc., Taketoyo, Aichi 470-23, Japan [T. I.]

Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), an alkylating antitumor agent the primary target of which has been thought to be DNA, resulted in elevated expression of mRNA for multidrug resistance-associated protein (MRP) within the first 2 h and then a decrease in expression 24 h after the treatment. Western blot analyses revealed that levels of MRP in these ACNU-treated cells paralleled mRNA levels. Membrane vesicles prepared from ACNU-treated cells also displayed elevated transport activities for leukotriene C₄, a known substrate for MRP. -Glutamylcysteine synthetase (-GCS) mRNA expression was coinduced with MRP by ACNU. Because -GCS is the rate-limiting enzyme involved in the de novo biosynthesis of glutathione, increases in glutathione were also transiently induced by ACNU. These results demonstrate for the first time that the expression of functional MRP and -GCS can be transiently coinduced by ACNU. Multiple short exposures (1 h) of ACNU following a long duration (1 week) of drug-free conditions resulted in the development of an ACNU-resistant population (designated A172R) that overexpressed MRP/-GCS mRNA and had elevated transport activities for leukotriene C₄. A172R exhibited cross-resistance to the antitumor drug doxorubicin and heavy metal sodium arsenate but not to cisplatin. Our results also demonstrate that intermittent treatments of human glioma cells with ACNU can lead to the development of MRP-related multidrug resistance. These results, taken together, reveal a possible new mechanism of the development of drug resistance for the antitumor nitrosoureas.

¹ This study was supported in part by National Cancer Institute Research Grants RO1 CA60486, CA72404, and CA16672 (institutional core).

² To whom requests for reprints should be addressed, at Department of Molecular Pathology, Box 89, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-3256; Fax: (713) 794-4672; E-mail: t_kuo@path.mda.tmc.edu.

Received 4/ 7/97. Accepted 9/26/97.

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