Hill Richard E, de Avila David M, Bertrand Kevin P, Greenberg Norman M, Reeves Jerry J
Department of Animal Sciences, Washington State University, Pullman, Washington 99164, USA.
Exp Biol Med (Maywood). 2003 Jul;228(7):818-22. doi: 10.1177/15353702-0322807-07.
This study was undertaken to test the effect of immunization against luteinizing hormone-releasing hormone (LHRH) fusion proteins on the development and progression of prostate cancer in the transgenic adenocarcinoma mouse prostate (TRAMP) model. Two LHRH fusion proteins, ovalbumin with seven LHRH peptides (OV-LHRH-7), and thioredoxin with seven LHRH peptides (TH-LHRH-7) were used in a cocktail vaccine. Two groups of male TRAMP mice were immunized with the cocktail. Primary immunizations were at either 4 or 8 weeks of age. LHRH immunized mice (n=19) were compared with castrated (n=19) and intact mice (n=18) for testosterone concentration, tumor weight, and lifespan. Immunization against LHRH in the TRAMP mice resulted in significant production of antibodies to LHRH compared with surgically castrated and intact control mice. Testicular weight was significantly reduced in the LHRH immunized groups compared with intact control mice. Serum testosterone was reduced (P<0.05) in the immunized mice compared with intact control mice and was not different from that of castrated mice (P>0.05). Tumor weight was variable and inconsistent throughout all treatment groups. Lifespan was not increased by immunization against LHRH or castration. Intact control mice (lived the longest (227+/-11 days), whereas immunized mice lived 206+/-11 days and castrated mice lived 213+/-13 days. Tumors from immunized TRAMP mice appeared more aggressive than tumors of castrated and intact mice, as demonstrated by 35% expression of gross lung tumors in the immunized mice whereas none were observed in the castrated or intact TRAMP mice. Prostate cancer is initially dependent upon androgens for growth and development, but cells have the ability to escape androgen dependence and progress to an androgen independent state, which was evident in this study. The TRAMP mouse model immunized against LHRH may have utility in future studies and treatments of the androgen independent prostate cancer.
本研究旨在测试针对促黄体生成素释放激素（LHRH）融合蛋白的免疫接种对转基因腺癌小鼠前列腺（TRAMP）模型中前列腺癌发生和进展的影响。两种LHRH融合蛋白，即带有七个LHRH肽的卵清蛋白（OV-LHRH-7）和带有七个LHRH肽的硫氧还蛋白（TH-LHRH-7）被用于一种联合疫苗中。两组雄性TRAMP小鼠用该联合疫苗进行免疫接种。初次免疫接种在4周龄或8周龄时进行。将LHRH免疫接种的小鼠（n = 19）与去势小鼠（n = 19）和未处理小鼠（n = 18）比较睾酮浓度、肿瘤重量和寿命。与手术去势和未处理的对照小鼠相比，TRAMP小鼠中针对LHRH的免疫接种导致产生了大量针对LHRH的抗体。与未处理的对照小鼠相比，LHRH免疫接种组的睾丸重量显著降低。与未处理的对照小鼠相比，免疫接种小鼠的血清睾酮降低（P<0.05），且与去势小鼠的血清睾酮无差异（P > 0.05）。所有治疗组的肿瘤重量各不相同且不稳定。针对LHRH的免疫接种或去势均未延长寿命。未处理的对照小鼠存活时间最长（227±11天），而免疫接种小鼠存活206±11天，去势小鼠存活213±13天。免疫接种的TRAMP小鼠的肿瘤比去势和未处理小鼠的肿瘤表现出更强的侵袭性，免疫接种小鼠中35%出现肉眼可见的肺肿瘤，而去势或未处理的TRAMP小鼠中均未观察到。前列腺癌最初依赖雄激素生长和发展，但细胞有能力逃避雄激素依赖并进展到雄激素非依赖状态，本研究中这一点很明显。针对LHRH免疫接种的TRAMP小鼠模型可能在未来雄激素非依赖型前列腺癌的研究和治疗中具有应用价值。
