RT Journal Article
SR Electronic
T1 Mechanism of Action and Preclinical Antitumor Activity of the Novel Hypoxia-Activated DNA Cross-Linking Agent PR-104
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 3922
OP 3932
DO 10.1158/1078-0432.CCR-07-0478
VO 13
IS 13
A1 Patterson, Adam V.
A1 Ferry, Dianne M.
A1 Edmunds, Shelley J.
A1 Gu, Yongchuan
A1 Singleton, Rachelle S.
A1 Patel, Kashyap
A1 Pullen, Susan M.
A1 Hicks, Kevin O.
A1 Syddall, Sophie P.
A1 Atwell, Graham J.
A1 Yang, Shangjin
A1 Denny, William A.
A1 Wilson, William R.
YR 2007
UL http://clincancerres.aacrjournals.org/content/13/13/3922.abstract
AB 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 γH2AX 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.