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Inhibition of Cyclin D1 Expression in Human Pancreatic Cancer Cells Is Associated with Increased Chemosensitivity and Decreased Expression of Multiple Chemoresistance Genes¹

Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine, Biological Chemistry, and Pharmacology, University of California, Irvine, California 92697 [M. Korn., M. Korc]; Department of Biochemistry, Kenneth Norris Jr. Cancer Hospital and Research Institute, University of Southern California School of Medicine, Los Angeles, California 90033 [K. D. D., P. V. D.]; Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, 64239 Israel [N. A.]; and Department of General Surgery, University of Ulm, 89075 Ulm, Germany [H. G. B.]

Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Inhibition of cyclin D1 expression has been recently shown (M. Kornmann, et al., J. Clin. Invest., 101: 344–352, 1998) to suppress pancreatic cancer cell growth and increase cytotoxic actions of cisplatinum. The aim of the present study was to determine whether inhibition of cyclin D1 expression also modulates the effects of other antineoplastic drugs and whether it is associated with alterations in the level of expression of drug resistance genes. The suppression of cyclin D1 expression after the stable transfection of a cyclin D1 antisense construct in PANC-1 and COLO-357 human pancreatic cancer cells resulted in a significant increase in sensitivity to the fluoropyrimidines 5-fluorouracil and 5-fluoro-2'-deoxyuridine and to mitoxantrone. All of the antisense-expressing clones exhibited a decrease in thymidylate synthase and an increase in thymidine phosphorylase mRNA expression as determined by reverse transcription-PCR analysis and decreased levels of MDR-1 and MRP mRNA as determined by Northern blotting. These findings demonstrate that the inhibition of cyclin D1, in addition to suppressing the growth of pancreatic cancer cells, enhances their responsiveness to multiple chemotherapeutic agents and suggest that this effect may be due to the altered expression of several chemoresistance genes.

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