Interleukin-4 receptor-targeted cytotoxin therapy of androgen-dependent and -independent prostate carcinoma in xenograft models.

Abstract

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, IC(50) 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-4Ralpha, 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 micro g/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 micro g/kg) given five QD injections. Administration of IL4-CTx i.t. (500 micro g/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 mm(2)) 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.

• Authors: Syed R Husain, Koji Kawakami, Mariko Kawakami, Raj K Puri
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 2 Issue 3 Pg. 245-54 (Mar 2003) ISSN: 1535-7163 [Print] United States
• PMID: 12657719 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Immunotoxins
• RNA, Messenger
• Receptors, Interleukin-4
• Recombinant Proteins
• interleukin 4 (38-37)-PE38KDEL
• Interleukin-4

Topics

• Animals
• Apoptosis (drug effects)
• Humans
• Immunoenzyme Techniques
• Immunotoxins (therapeutic use)
• Interleukin-4 (metabolism)
• Male
• Mice
• Mice, Nude
• Necrosis
• Neoplasms, Hormone-Dependent (drug therapy, genetics, metabolism)
• Prostatic Hyperplasia (drug therapy, genetics, metabolism)
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• RNA, Messenger (metabolism)
• Receptors, Interleukin-4 (metabolism)
• Recombinant Proteins (therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection
• Transplantation, Heterologous
• Tumor Cells, Cultured (transplantation)