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¹ Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; ² Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; and ³ Medical Oncology Clinical Research Unit, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Esther H. Chang, Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Research Building, E420, 3970 Reservoir Road Northwest, Washington, DC 20007-2197. Phone: 202-687-8418; Fax: 202-687-8434. E-mail: change{at}georgetown.edu

Folates are essential for cell survival and are required for numerous biochemical processes. The human isoform folate receptor (hFR) has a very high affinity for folic acid and is considered an essential component in the cellular accumulation of folates and folate analogues used in chemotherapy. The expression of hFR is not detected inmost normal tissues. In contrast, high levels of the expression of hFR have been reported in a variety of cancer cells. The significance of hFR overexpression in malignant tissues has not been elucidated, but it is possible that it promotes cell proliferation not only by mediating folate uptake but also by generating other regulatory signals. The purpose of the present study was to evaluate hFR as a potential target for the treatment of breast cancer. Initial studies were done in nasopharyngeal carcinoma (KB) cells, which express high levels of hFR. In KB cells, antisense oligodeoxyribonucleotides (ODN) complementary to the hFR gene sequences were found to reduce newly synthesized hFR protein up to 60%. To examine the effect of hFR antisense ODNs in a panel of cultured human breast cancer cell lines, we used a tumor cell–targeted, transferrin-liposome–mediated delivery system. The data show that hFR antisense ODNs induced a dose-dependent decrease in cell survival. Finally, we determined that hFR antisense ODNs sensitized MDA-MB-435 breast cancer cells by 5-fold to treatment with doxorubicin. The data support the application of hFR antisense ODNs as a potential anticancer agent in combination with doxorubicin.

Key Words: doxorubicin • 07-06-02 antisense oligonucleotides

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Received 2/11/03; revised 9/23/04; accepted 10/ 7/04.