新型缺氧激活的DNA交联剂PR-104的作用机理和临床前抗肿瘤活性。,Clinical Cancer Research

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新型缺氧激活的DNA交联剂PR-104的作用机理和临床前抗肿瘤活性。
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2007 Jul 1 , DOI: 10.1158/1078-0432.ccr-07-0478
Adam V. Patterson ₁ , Dianne M. Ferry ₁ , Shelley J. Edmunds ₁ , Yongchuan Gu ₁ , Rachelle S. Singleton ₁ , Kashyap Patel ₁ , Susan M. Pullen ₁ , Kevin O. Hicks ₁ , Sophie P. Syddall ₁ , Graham J. Atwell ₁ , Shangjin Yang ₁ , William A. Denny ₁ , William R. Wilson ₁

Affiliation

目的：缺氧是实体瘤的特征，并且是潜在的重要治疗靶标。在这里，我们表征了新型缺氧激活的前药3,5-二硝基苯甲酰胺氮芥子PR-104的作用机理和临床前抗肿瘤活性，该药物最近已进入临床试验。实验设计：使用10种人类肿瘤细胞系评估了体外细胞毒性。SiHa细胞通过液相色谱-质谱法在缺氧条件下表征代谢，并通过彗星分析和gammaH2AX形成来表征DNA损伤。在治疗后18小时通过克隆形成试验或通过肿瘤生长延迟，在多种异种移植模型（PR-104 +/-放射或化学疗法）中评估了抗肿瘤活性。结果：磷酸酯“前药” PR-104在小鼠中具有良好的耐受性，并迅速转化为相应的前药PR-104A。PR-104A的细胞毒性在体外因缺氧而增加了10到100倍。还原为主要的细胞内代谢产物羟胺PR-104H，可在缺氧条件下选择性地使DNA交联。PR-104H与氯离子的反应产生了亲脂性细胞毒性代谢物，潜在地可以提供旁观者效应。在肿瘤切除试验中，在同等宿主毒性下，PR-104在异种移植物（HT29，SiHa和H460）中对缺氧（抗辐射）和好氧细胞的杀灭作用比替拉帕明或常规芥菜更大。PR-104在八种异种移植模型中的六种中显示出单药活性，并且与可能保留缺氧细胞的药物（吉西他滨合并Panc-01胰腺肿瘤，多西他赛合并22RV1前列腺肿瘤）联合使用时表现出大于加和的抗肿瘤活性。结论：PR-104是一种新型的缺氧激活的DNA交联剂，具有明显的针对人肿瘤异种移植的活性，既可以作为单一疗法，也可以与放射疗法和化学疗法相结合。

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Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104.

PURPOSE: Hypoxia is a characteristic of solid tumors and a potentially important therapeutic target. Here, we characterize the mechanism of action and preclinical antitumor activity of a novel hypoxia-activated prodrug, the 3,5-dinitrobenzamide nitrogen mustard PR-104, which has recently entered clinical trials. EXPERIMENTAL DESIGN: Cytotoxicity in vitro was evaluated using 10 human tumor cell lines. SiHa cells were used to characterize metabolism under hypoxia, by liquid chromatography-mass spectrometry, and DNA damage by comet assay and gammaH2AX formation. Antitumor activity was evaluated in multiple xenograft models (PR-104 +/- radiation or chemotherapy) by clonogenic assay 18 h after treatment or by tumor growth delay. RESULTS: The phosphate ester "pre-prodrug" PR-104 was well tolerated in mice and converted rapidly to the corresponding prodrug PR-104A. The cytotoxicity of PR-104A was increased 10- to 100-fold by hypoxia in vitro. Reduction to the major intracellular metabolite, hydroxylamine PR-104H, resulted in DNA cross-linking selectively under hypoxia. Reaction of PR-104H with chloride ion gave lipophilic cytotoxic metabolites potentially able to provide bystander effects. In tumor excision assays, PR-104 provided greater killing of hypoxic (radioresistant) and aerobic cells in xenografts (HT29, SiHa, and H460) than tirapazamine or conventional mustards at equivalent host toxicity. PR-104 showed single-agent activity in six of eight xenograft models and greater than additive antitumor activity in combination with drugs likely to spare hypoxic cells (gemcitabine with Panc-01 pancreatic tumors and docetaxel with 22RV1 prostate tumors). CONCLUSIONS: PR-104 is a novel hypoxia-activated DNA cross-linking agent with marked activity against human tumor xenografts, both as monotherapy and combined with radiotherapy and chemotherapy.

更新日期：2017-01-31

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