Evaluating hypoxia-inducible factor-1α as a cancer therapeutic target via inducible RNA interference in vivo

被引：89

作者：

Li, LM ^{[1
]}

Lin, XY ^{[1
]}

Staver, M ^{[1
]}

Shoemaker, A ^{[1
]}

Semizarov, D ^{[1
]}

Fesik, SW ^{[1
]}

Shen, Y ^{[1
]}

机构：

[1] Abbott Labs, Abbott Pk, IL 60064 USA

来源：

CANCER RESEARCH | 2005年 / 65卷 / 16期

关键词：

D O I：

10.1158/0008-5472.CAN-04-4426

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Validating potential targets is an important step in the drug discovery process. In this study, we tested the feasibility of using inducible RNA interference (RNAi) in vivo to obtain an unbiased evaluation on the efficacy of inhibiting hypoxia-inducible factor-1 alpha (HIF-1 alpha) in established tumors. We showed that HIF-1 alpha inhibition resulted in transient tumor stasis or tumor regression, and inhibiting HIF-1 alpha in early-stage tumors was found to be more efficacious than inhibiting HIF-1 alpha in more established tumors. A differential requirement of HIF-1 alpha for tumor growth was also observed among different tumor types. Examination of tumors resistant to HIF-1 alpha inhibition suggested that the resistance might result from a less hypoxic tumor environment and the level of HIF-1 alpha expression in tumors may be a useful marker for predicting tumor response to HIF-1 inhibition. This study shows that inducible RNAi is a versatile tool for evaluating cancer targets in vivo. In addition to broad implications on in vivo validation of cancer targets, results from this study will also be instructive for practical applications of HIF-1-based cancer therapeutics.

引用

页码：7249 / 7258

页数：10

共 26 条

[1] The hypoxic response of tumors is dependent on their microenvironment [J].