Vaccine Research Institute of San Diego, San Diego, California 92121, USA.
Prostate. 2011 Jun 1;71(8):813-23. doi: 10.1002/pros.21297. Epub 2010 Nov 4.
Hormonal ablation is the standard of treatment for advanced androgen-dependent prostate cancer. Although tumor regression is usually achieved at first, the cancer inevitably evolves toward androgen-independence, in part because of the development of mechanisms of resistance and in part because at the tissue level androgen withdrawal is not fully attained. Current research efforts are focused on new therapeutic strategies that will increase the effectiveness of androgen withdrawal and delay recurrence. We used a syngeneic pseudo-orthotropic mouse model of prostate cancer to test the efficacy of combining androgen withdrawal with FDA-approved COX-2 inhibitor celecoxib.
GFP-tagged TRAMP-C2 cells were co-implanted with prostate tissue in the dorsal chamber model and tumors were allowed to establish and vascularize. Tumor growth and angiogenesis were monitored in real-time using fluorescent intravital microscopy (IVM). Androgen withdrawal in mice was achieved using surgical castration or chemical hormonal ablation, alone or in combination with celecoxib (15 mg/kg, twice daily).
Celecoxib alone decreased the growth of prostate tumors mostly by inducing mitotic failure, which resulted in increased apoptosis. Surprisingly, celecoxib did not possess significant angiostatic activity. Surgical or chemical castration prevented the growth of prostate tumors and this, on the other hand, was associated with disruption of the tumor vasculature. Finally, androgen withdrawal combined with celecoxib caused tumor regression through decreased angiogenesis and increased mitosis arrest and apoptosis.
Celecoxib, a relatively safe COX-2-selective anti-inflammatory drug, significantly increases the efficacy of androgen withdrawal in vivo and warrants further investigation as a complement therapy for advanced prostate cancer.
激素消融是治疗晚期雄激素依赖性前列腺癌的标准方法。虽然最初通常会实现肿瘤消退，但癌症不可避免地会向雄激素不依赖性发展，部分原因是耐药机制的发展，部分原因是在组织水平上雄激素去除不完全。目前的研究重点是新的治疗策略，这些策略将提高雄激素去除的效果并延迟复发。我们使用前列腺癌同源异位小鼠模型来测试联合雄激素去除与 FDA 批准的 COX-2 抑制剂塞来昔布的疗效。
GFP 标记的 TRAMP-C2 细胞与前列腺组织一起植入背室模型中，并允许肿瘤建立和血管化。使用荧光活体显微镜（IVM）实时监测肿瘤生长和血管生成。通过手术去势或化学激素消融单独或与塞来昔布（15mg/kg，每日两次）联合，在小鼠中进行雄激素去除。
塞来昔布单独使用主要通过诱导有丝分裂失败来抑制前列腺肿瘤的生长，从而导致细胞凋亡增加。令人惊讶的是，塞来昔布没有明显的血管生成抑制活性。手术或化学去势可预防前列腺肿瘤的生长，而这反过来又与肿瘤血管破坏有关。最后，雄激素去除联合塞来昔布通过减少血管生成和增加有丝分裂停滞和细胞凋亡导致肿瘤消退。
塞来昔布是一种相对安全的 COX-2 选择性抗炎药物，可显著提高体内雄激素去除的疗效，值得进一步研究作为晚期前列腺癌的补充治疗。
