The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada.
Prostate. 2012 Jun 1;72(8):875-85. doi: 10.1002/pros.21490. Epub 2011 Oct 5.
Response to bicalutamide after castration failure is not durable and treatment options at this stage are limited. Carbidopa, an L-dopa decarboxylase (AR-coactivator) inhibitor, has been shown to retard prostate tumor growth/PSA production in xenografts. Here, we hypothesize that pharmacological targeting of the AR-axis by combination treatment with bicalutamide plus carbidopa significantly enhances antitumoral activity in vitro and in vivo compared to monotherapy with either drug.
Carbidopa was tested for its ability to enhance the effects of bicalutamide on cell viability, apoptosis and PSA transactivation in LNCaP and C4-2 cells. The castration-resistant prostate cancer (CRPC) LNCaP xenograft tumor model was used in vivo. After CRPC progression, mice were treated with carbidopa (50 mg/kg) and bicalutamide (50 mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly.
Combination treatment of carbidopa plus bicalutamide significantly inhibited cell viability in both cell lines and induced apoptosis. The combination treatment also decreased androgen-induced PSA transactivation by 62.6% in LNCaP cells and by 55.6% in C4-2 cells compared to control, while bicalutamide monotherapy reduced PSA levels by 27.5% and 29.1% in LNCaP and C4-2 cells. In vivo, bicalutamide monotherapy delayed LNCaP CRPC tumor growth rate by 72.2%, while combination treatment reduced tumor growth by 84.4% compared to control. Serum PSA was also reduced 70.6% with bicalutamide monotherapy, while combination therapy reduced PSA levels by 76.7% compared to control.
This study demonstrates preclinical proof-of-principle that pharmacological targeting of prostate tumors by combination treatment of bicalutamide plus carbidopa significantly reduces AR activity, and thereby delays CRPC tumor progression in vivo.
去势治疗失败后对比卡鲁胺的反应并不持久，且在此阶段的治疗选择有限。卡比多巴（一种 L-多巴脱羧酶（AR 共激活剂）抑制剂）已被证明可延缓异种移植物中的前列腺肿瘤生长/PSA 产生。在这里，我们假设通过联合比卡鲁胺加卡比多巴对 AR 轴进行药物靶向治疗，与单独使用任一种药物相比，可显著增强体外和体内的抗肿瘤活性。
检测卡比多巴增强比卡鲁胺对 LNCaP 和 C4-2 细胞活力、细胞凋亡和 PSA 反式激活的作用的能力。在去势抵抗性前列腺癌（CRPC）LNCaP 异种移植肿瘤模型中进行体内研究。在 CRPC 进展后，用卡比多巴（50mg/kg）和比卡鲁胺（50mg/kg）单独或联合治疗小鼠。每周评估肿瘤体积和血清 PSA。
卡比多巴联合比卡鲁胺治疗显著抑制了两种细胞系中的细胞活力，并诱导了细胞凋亡。与对照组相比，联合治疗还使 LNCaP 细胞中雄激素诱导的 PSA 反式激活减少了 62.6%，在 C4-2 细胞中减少了 55.6%，而比卡鲁胺单药治疗使 LNCaP 和 C4-2 细胞中的 PSA 水平分别降低了 27.5%和 29.1%。在体内，比卡鲁胺单药治疗使 LNCaP CRPC 肿瘤生长速度延迟了 72.2%，而联合治疗使肿瘤生长速度比对照组降低了 84.4%。与对照组相比，血清 PSA 也降低了 70.6%，而联合治疗降低了 76.7%。
这项研究提供了临床前原理验证，即通过联合比卡鲁胺加卡比多巴对前列腺肿瘤进行药物靶向治疗，可显著降低 AR 活性，从而延缓体内 CRPC 肿瘤的进展。
