BIOLOGY CONTRIBUTION SELENITE TREATMENT INHIBITS LAPC-4 TUMOR GROWTH AND PROSTATE-SPECIFIC ANTIGEN SECRETION IN A XENOGRAFT MODEL OF HUMAN PROSTATE CANCER RUMI S. BHATTACHARYYA,PH.D., y BRYAN HUSBECK,PH.D.,* DAVID FELDMAN, M.D., y AND SUSAN J. KNOX,PH.D., M.D.* Departments of *Radiation Oncology and y Endocrinology, Stanford University, Stanford, CA Purpose: Selenium compounds have known chemopreventive effects on prostate cancer. However selenite, an in- organic form of selenium, has not been extensively studied as a treatment option for prostate cancer. Our previous studies have demonstrated the inhibition of androgen receptor expression and androgen stimulated prostate-spe- cific antigen (PSA) expression by selenite in human prostate cancer cell lines. In this study, we investigated the in vivo effects of selenite as a therapy to treat mice with established LAPC-4 tumors. Methods and Materials: Male mice harboring androgen-dependent LAPC-4 xenograft tumors were treated with selenite (2 mg/kg intraperitoneally three times per week) or vehicle for 42 days. In addition, androgen-independent LAPC-4 xenograft tumors were generated in female mice over 4 to 6 months. Once established, androgen-indepen- dent LAPC-4 tumor fragments were passaged into female mice and were treated with selenite or vehicle for 42 days. Changes in tumor volume and serum PSA levels were assessed. Results: Selenite significantly decreased androgen-dependent LAPC-4 tumor growth in male mice over 42 days (p < 0.001). Relative tumor volume was decreased by 41% in selenite-treated animals compared with vehicle- treated animals. The inhibition of LAPC-4 tumor growth corresponded to a marked decrease in serum PSA levels (p < 0.01). In the androgen-independent LAPC-4 tumors in female mice, selenite treatment decreased tumor volume by 58% after 42 days of treatment (p < 0.001). Conclusions: These results suggest that selenite may have potential as a novel therapeutic agent to treat both androgen-dependent and androgen-independent prostate cancer. Ó 2008 Elsevier Inc. Prostate cancer, LAPC-4 xenograft, Selenite, PSA, Androgen-independent prostate cancer. INTRODUCTION Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer death in men in the United States (1). Selenium is an essential component of a number of functional selenoproteins required for normal heath. Epidemiologic studies suggest that an inverse relation- ship exists between serum selenium levels and cancer risk (2, 3). Results from the Nutritional Prevention of Cancer Trial re- vealed that selenium supplementation (200 mg/day) resulted in a 49% reduction of PCa incidence (4, 5). This information has led to the ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT) which is evaluating whether daily selenium supplementation, alone or in combination with vitamin E, will decrease the incidence of PCa (6). In addition to the SE- LECT trial, a ‘‘watchful waiting’’ trial is also being conducted to study the effect of selenium on the progression of clinical PCa, using time to disease progression and prostate-specific antigen (PSA) velocity as the primary endpoints (7). Selenium compounds have been shown to inhibit tumor development and growth in a variety of in vivo models of PCa (3). In an in vivo canine model, selenium supplementa- tion for 7 months resulted in decreased DNA damage in pros- tatic epithelial cells and increased epithelial cell apoptosis (8). Selenium in the form of methylselenocysteine inhibited LNCaP tumor growth, androgen receptor (AR) expression, and PSA levels in nude mice (9). Selenate, an inorganic form of selenium, inhibited the growth of orthotopic PC-3 tu- mors developed in the prostates of male nude mice (10). Se- lenoprotein deficiency has also been studied for its effect on PCa. Transgenic mice with selenoprotein deficiencies de- velop PCa lesions at an accelerated rate compared with wild-type mice (11). Reprint requests to: Susan J. Knox, M.D., Ph.D., Department of Radiation Oncology, Stanford University Medical Center, 300 Pas- teur Drive, Stanford, CA, 94305. Tel: (650)725-2720; Fax: (650) 723-7382; E-mail: sknox@stanford.edu Conflict of interest: none. Acknowledgments—This research was supported by the Department of Defense Award Number W81XWH-04-1-0160. RSB was supported by a Department of Defense Postdoctoral Fellowship, Number W81XWH-05-1-0582. Views and opinions of, and en- dorsements by, the authors do not reflect those of the US Army or the Department of Defense. Received Jan 14, 2008, and in revised form June 25, 2008. Accepted for publication July 7, 2008. 935 Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 3, pp. 935–940, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter doi:10.1016/j.ijrobp.2008.07.005