Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program.
Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program.
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DOI：
10.1002/pbc.22921
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发表时间：
2011-09
影响因子：
3.2
通讯作者：
Smith, Malcolm A.
中科院分区：
文献类型：
--
作者：
Houghton, Peter J.;Lock, Richard;Carol, Hernan;Morton, Christopher L.;Phelps, Doris;Gorlick, Richard;Kolb, E. Anders;Keir, Stephen T.;Reynolds, C. Patrick;Kang, Min H.;Maris, John M.;Wozniak, Amy W.;Gu, Yongchuan;Wilson, William R.;Smith, Malcolm A.
PR-104在体内迅速水解为PR-104A，PR-104A通过还原成相应的5-羟胺(PR-104H)和胺(PR-104M)而被激活，产生DNA链间交联。 PR-104 的激活可以通过缺氧依赖性还原酶发生，也可以通过醛酮还原酶 (AKR) 1C3 独立于缺氧发生。 PR-104A 与 PPTP 体外组（10 nM 至 100 μM）和 PR-104 进行体内测试，每周 6 次，最大耐受剂量 (MTD) 为 550 mg/kg。随后在 270 和 110 mg/kg 下测试 PR-104。确定了 PR-104 及其代谢物的药代动力学，以及异种移植物中 AKR1C3 RNA 和蛋白质的水平。在体外，白血病模型对 PR-104A 最敏感。在体内，PR-104 在 21/34 实体瘤模型中诱导达到其 MTD 的客观反应，并对 7/7 急性淋巴细胞白血病 (ALL) 模型保持完全反应。在 270 mg/kg 和更低的剂量水平下，PR-104 没有诱导实体瘤消退，表明存在陡峭的剂量反应关系。药代动力学分析表明，与患者相比，小鼠体内 PR-104A 及其代谢物的全身暴露量更高。 AKR1C3 蛋白水平与肿瘤反应性不相关。作为单一疗法，PR-104 在其 MTD 下对实体瘤和 ALL 模型均表现出高水平的活性，但在实体瘤 MTD 剂量的一半时，活性几乎完全丧失。 PR-104 MTD 人体试验的药代动力学数据表明，PR-104 代谢物可能无法达到与高水平临床前活性相关的儿童血浆暴露量。
PR-104 is rapidly hydrolyzed to PR-104A in vivo, which is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and amine (PR-104M) to produce DNA interstrand cross-links. PR-104 activation can occur via hypoxia-dependent reductases and also independently of hypoxia by aldo-keto reductase (AKR) 1C3. PR-104A was tested against the PPTP in vitro panel (10 nM to 100 μM), and PR-104 in vivo using a weekly × 6 schedule at its maximum tolerated dose (MTD) of 550 mg/kg. Subsequently PR-104 was tested at 270 and 110 mg/kg. Pharmacokinetics for PR-104 and its metabolites were determined, as were levels of AKR1C3 RNA and protein in xenografts. In vitro, the leukemia models were most sensitive to PR-104A. In vivo, PR-104 induced objective responses at its MTD in 21/34 solid tumor models and maintained complete responses against 7/7 acute lymphoblastic leukemia (ALL) models. At 270 mg/kg and lower dose levels, PR-104 did not induce solid tumor regressions, suggesting a steep dose–response relationship. Pharmacokinetic analysis suggests higher systemic exposures to PR-104A and its metabolites in mice compared to those achievable in patients. Levels of AKR1C3 protein did not correlate with tumor responsiveness. As monotherapy, PR-104 demonstrated a high level of activity against both solid tumor and ALL models at its MTD, but the activity was almost completely lost at half the MTD dose for solid tumors. Pharmacokinetic data at the PR-104 MTD from human trials suggest that PR-104 metabolites may not reach the plasma exposures in children that were associated with high-level preclinical activity.
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影响因子：
3.2
作者：
Houghton, Peter J.;Morton, Christopher L.;Smith, Malcolm A.
通讯作者：
Smith, Malcolm A.
影响因子：
2.4
作者：
Denny, WA
通讯作者：
Denny, WA
影响因子：
5.8
作者：
Guise, Chris P.;Wang, Anderson T.;Patterson, Adam V.
通讯作者：
Patterson, Adam V.
影响因子：
3.4
作者：
Chow, DC;Wenning, LA;Papoutsakis, ET
通讯作者：
Papoutsakis, ET
影响因子：
3.9
作者：
Gu, Yongchuan;Atwell, Graham J.;Wilson, William R.
通讯作者：
Wilson, William R.