局部晚期和转移性膀胱癌(BC)的当前标准护理系统治疗方案,主要基于顺铂-吉西他滨组合,受到严重的治疗失败率和基于虚弱的患者不合格的限制。我们以前使用药物筛选方法解决了对耐受性更好的BC治疗策略的迫切临床需求,在BC的临床前模型中鉴定出氯法拉滨的优异抗肿瘤活性。为了进一步评估氯法拉滨作为潜在的BC治疗成分,我们在临床前体外和体内BC模型中对氯法拉滨与吉西他滨的反应进行了头对头比较,辅以计算机模拟分析。体外数据表明两种抗代谢物之间存在明显的相关性,吉西他滨具有较高的细胞毒性,特别是针对几种非恶性细胞类型,包括角质形成细胞和内皮细胞。因此,在患者来源的BC异种移植模型中,氯法拉滨(口服或腹膜内给药)的耐受性明显优于吉西他滨(腹膜内给药).氯法拉滨还表现出明显优越的抗癌功效,即使在吉西他滨优化的给药方案。既不能完全缓解也不能治愈,两者都是用氯法拉滨观察到的,任何可耐受的吉西他滨方案均可实现。一起来看,我们的研究结果表明,氯法拉滨比吉西他滨具有更好的治疗窗口,进一步强调其作为BC药物再利用的候选药物的潜力。患者总结:我们比较了氯法拉滨的抗癌活性,一种用于治疗白血病而非膀胱癌的药物,和吉西他滨,目前用于膀胱癌化疗的药物。使用细胞培养和小鼠模型,我们发现氯法拉滨比吉西他滨具有更好的耐受性和有效性,甚至在小鼠模型中治愈了植入的肿瘤。我们的结果表明氯法拉滨,单独或组合方案,可能优于吉西他滨治疗膀胱癌。
Current standard-of-care systemic therapy options for locally advanced and metastatic bladder cancer (BC), which are predominantly based on cisplatin-gemcitabine combinations, are limited by significant treatment failure rates and frailty-based patient ineligibility. We previously addressed the urgent clinical need for better-tolerated BC therapeutic strategies using a drug screening approach, which identified outstanding antineoplastic activity of clofarabine in preclinical models of BC. To further assess
clofarabine as a potential BC therapy component, we conducted head-to-head comparisons of responses to clofarabine versus gemcitabine in preclinical in vitro and in vivo models of BC, complemented by in silico analyses. In vitro data suggest a distinct correlation between the two antimetabolites, with higher cytotoxicity of gemcitabine, especially against several nonmalignant cell types, including keratinocytes and endothelial cells. Accordingly, tolerance of
clofarabine (oral or intraperitoneal application) was distinctly better than for gemcitabine (intraperitoneal) in patient-derived xenograft models of BC.
Clofarabine also exhibited distinctly superior anticancer efficacy, even at dosing regimens optimized for gemcitabine. Neither complete remission nor cure, both of which were observed with
clofarabine, were achieved with any tolerable gemcitabine regimen. Taken together, our findings demonstrate that clofarabine has a better therapeutic window than gemcitabine, further emphasizing its potential as a candidate for drug repurposing in BC. PATIENT SUMMARY: We compared the anticancer activity of clofarabine, a drug used for treatment of leukemia but not bladder cancer, and gemcitabine, a drug currently used for chemotherapy against bladder cancer. Using cell cultures and mouse models, we found that clofarabine was better tolerated and more efficacious than gemcitabine, and even cured implanted tumors in mouse models. Our results suggest that
clofarabine, alone or in combination schemes, might be superior to gemcitabine for the treatment of bladder cancer.