Pharmatest Services Ltd., 20520 Turku, Finland.
Aurexel Life Sciences Ltd., 21240 Askainen, Finland.
Int J Mol Sci. 2023 Jan 22;24(3):2189. doi: 10.3390/ijms24032189.
Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy. The combination of radium-223 and enzalutamide also demonstrated enhanced antitumor efficacy, as determined by measuring serum PSA levels in the intratibial LNCaP model. A decreasing trend in the total area of tumor-induced abnormal bone was associated with the combination treatment. The serum levels of the bone formation marker PINP and the bone resorption marker CTX-I were lowest in the combination treatment group and markedly decreased compared with vehicle group. Concurrent administration of enzalutamide did not impair radium-223 uptake in tumor-bearing bone or the ability of radium-223 to inhibit tumor-induced abnormal bone formation. In conclusion, combination treatment with radium-223 and enzalutamide demonstrated enhanced antitumor efficacy without compromising the integrity of healthy bone. The results support the ongoing phase 3 trial of this combination.
镭-223 二氯化物和恩扎鲁胺被用于治疗转移性去势抵抗性前列腺癌，它们的联合应用目前正在一项大型 3 期临床试验中进行研究。在这里，我们评估了镭-223、恩扎鲁胺及其联合应用在模拟前列腺癌骨转移的胫骨内 LNCaP 模型中的抗肿瘤疗效。实验表明，镭-223 和恩扎鲁胺联合抑制了 LNCaP 细胞增殖，并表现出协同疗效。在胫骨内 LNCaP 模型中，通过测量血清 PSA 水平，联合治疗也显示出增强的抗肿瘤疗效。与单独治疗相比，肿瘤诱导的异常骨总面积减少与联合治疗相关。骨形成标志物 PINP 和骨吸收标志物 CTX-I 的血清水平在联合治疗组最低，并与对照组相比明显下降。同时给予恩扎鲁胺不会损害肿瘤骨中镭-223 的摄取，也不会影响镭-223 抑制肿瘤诱导的异常骨形成的能力。总之，镭-223 和恩扎鲁胺的联合治疗在不损害健康骨完整性的情况下，增强了抗肿瘤疗效。这些结果支持该联合治疗的正在进行的 3 期临床试验。
