Michael Gutmann, Iris E Ertl, Paula Herek, Petra Vician, Christine Pirker, Christoph Nössing, Robert Brettner, Ursula Lemberger, Reinhard Grausenburger, Kai Batlogg, Oliver Baumfried, Isabella Prantl, Neha Singh, Ekaterina Laukhtina, André Oszwald, Gabriel Wasinger, Eva Compérat, Walter Berger, Shahrokh F Shariat, Bernhard Englinger
{"title":"Clofarabine Has a Superior Therapeutic Window as compared to Gemcitabine in Preclinical Bladder Cancer Models.","authors":"Michael Gutmann, Iris E Ertl, Paula Herek, Petra Vician, Christine Pirker, Christoph Nössing, Robert Brettner, Ursula Lemberger, Reinhard Grausenburger, Kai Batlogg, Oliver Baumfried, Isabella Prantl, Neha Singh, Ekaterina Laukhtina, André Oszwald, Gabriel Wasinger, Eva Compérat, Walter Berger, Shahrokh F Shariat, Bernhard Englinger","doi":"10.1016/j.euo.2024.05.001","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12256,"journal":{"name":"European urology oncology","volume":" ","pages":""},"PeriodicalIF":8.3000,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European urology oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.euo.2024.05.001","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
目前治疗局部晚期和转移性膀胱癌(BC)的标准系统疗法主要以顺铂-吉西他滨联合疗法为主,但由于治疗失败率高和患者体质虚弱而不符合治疗条件,这种疗法受到了限制。此前,我们利用药物筛选方法解决了临床对耐受性更好的巴比妥类药物治疗策略的迫切需求,并在巴比妥类药物临床前模型中发现了氯法拉滨出色的抗肿瘤活性。为了进一步评估氯法拉滨作为一种潜在的BC治疗成分,我们在BC临床前体外和体内模型中对氯法拉滨和吉西他滨的反应进行了正面比较,并辅以硅学分析。体外数据表明,这两种抗代谢药物之间存在明显的相关性,吉西他滨的细胞毒性更高,尤其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 BC 患者衍生异种移植模型中,氯法拉滨(口服或腹腔注射)的耐受性明显优于吉西他滨(腹腔注射)。氯法拉滨的抗癌疗效也明显优于吉西他滨,即使在吉西他滨的优化剂量方案中也是如此。在任何可耐受的吉西他滨治疗方案中,氯法拉滨都无法实现完全缓解或治愈。综上所述,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期,进一步凸显了其作为治疗 BC 的候选药物的潜力。患者摘要:我们比较了氯法拉滨和吉西他滨的抗癌活性,氯法拉滨是一种用于治疗白血病但不用于治疗膀胱癌的药物,而吉西他滨是一种目前用于化疗膀胱癌的药物。通过使用细胞培养物和小鼠模型,我们发现氯法拉滨比吉西他滨更耐受、更有效,甚至能治愈小鼠模型中的植入性肿瘤。我们的研究结果表明,在治疗膀胱癌方面,单独使用或联合使用氯法拉滨可能优于吉西他滨。
期刊介绍:
Journal Name: European Urology Oncology
Affiliation: Official Journal of the European Association of Urology
Focus:
First official publication of the EAU fully devoted to the study of genitourinary malignancies
Aims to deliver high-quality research
Content:
Includes original articles, opinion piece editorials, and invited reviews
Covers clinical, basic, and translational research
Publication Frequency: Six times a year in electronic format