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Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

² To whom requests for reprints should be addressed, at Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, NIH-Building 29B, Room 2NN10, 29 Lincoln Drive, MSC 4555, Bethesda, MD 20892. Phone: (301) 827-0471; Fax: (301) 827-0449; E-mail: Puri{at}cber.fda.gov

Prostate cancer is the most commonly diagnosed solid tumors in United States men. Survival with advanced prostate cancer is dismal because of a lack of effective treatments. Overexpression of interleukin 4 receptors (IL-4R) on prostate carcinoma cells makes them suitable targets for the interleukin 4 (IL-4) fused Pseudomonas exotoxin, IL-4 cytotoxin (IL4-CTx). Androgen-dependent (LNCaP) and -independent (DU145) human prostate cancer cell lines overexpress IL-4Rs and are exquisitely sensitive to IL4-CTx. Using LNCaP and DU145 cell lines, IC₅₀ values of 4.5 ± 2.0 and 6.5 ± 0.5 ng/ml, respectively, were obtained for IL4-CTx in protein synthesis inhibition assays. Primary cultures established from prostate tumor biopsies were equally sensitive to the cytotoxic effects of IL4-CTx. Reverse transcription-PCR analysis, although not quantitative, indicated the presence of mRNA for IL-4R, a primary subunit of the IL-4R receptor complex in prostate carcinoma cell lines, primary cultures, benign prostatic hyperplasia, and prostate carcinoma tissues. Immunohistochemistry studies revealed the presence of IL-4R in benign prostatic hyperplasia and prostate carcinomas. Five daily (QD) injections of IL4-CTx (100 µg/kg) administered i.v., i.p., or intratumoral (i.t.) caused several complete responses in nude mice with s.c. DU145 and LNCaP tumors. i.t. injections of IL4-CTx elicited tumor regression in a dose-dependent manner with complete responses occurring in 100% of the animals when treated with IL4-CTx (500 µg/kg) given five QD injections. Administration of IL4-CTx i.t. (500 µg/kg) either 10 times QD or six injections on alternate days elicited complete responses in 40% of mice with DU145 tumors that were three times larger (67 mm²) on initiation of treatments. IL4-CTx appeared to be well tolerated. On the basis of these results, combining i.t. injections of IL4-CTx with systemic administration may provide an effective strategy for treating patients with advanced, refractory prostate cancer.

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