Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer
Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer
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DOI：
10.1158/1078-0432.ccr-08-3317
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发表时间：
2009-08-01
影响因子：
11.5
通讯作者：
Bocci, Guido
中科院分区：
文献类型：
--
作者：
Fontana, Andrea;Galli, Luca;Bocci, Guido
目的：本研究的目的是评估在晚期激素难治性前列腺癌患者中，单次静脉注射标准剂量环磷酰胺（CTX）后立即口服节律性环磷酰胺（CTX）联合塞来昔布（CXB）和地塞米松（DEX）治疗的临床活性和药效学特征。实验设计：28名患者（68%多西他赛耐药）在第1天接受500 mg/m(2) CTX静脉注射，从第2天开始，CTX 50 mg/天，CXB 200 mg/天两次，DEX 1 mg/天，直到疾病进展。ELISA法检测血浆血管内皮生长因子（VEGF）和血小板spondin-1，实时逆转录- pcr检测外周血单个核细胞中VEGF和血小板spondin-1基因的表达以及血液样品中ve -钙粘蛋白（VE-C）的表达。结果：28例患者中有9例（32%）的前列腺特异性抗原比基线下降了50%。中位无进展生存期和总生存期分别为3个月（95%可信区间，2.2-4.2个月）和21个月（95%可信区间，12.4-29.4个月）。毒性较轻，未发生3 ~ 4级毒性。血浆VEGF与前列腺特异性抗原值有显著相关性（r = 0.4223; P < 0.001）。在无反应的患者中，VEGF水平显著升高，而在治疗开始后，有反应的患者与无反应的患者相比，VE-C基因表达水平显著降低。结论：节拍剂CTX联合CXB和DEX对患者具有良好的毒性和活性。VE-C基因表达和VEGF水平是临床反应的潜在有用的药效学标志物。
Purpose: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients.Experimental Design: Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m(2) CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood samples was done.Results: A confirmed prostate-specific antigen decrease of >= 50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P < 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones.Conclusion: Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response.