Details

Autor(en) / Beteiligte

• PATTERSON, Adam V
• FERRY, Dianne M
• SHANGJIN YANG
• DENNY, William A
• WILSON, William R
• EDMUNDS, Shelley J
• YONGCHUAN GU
• SINGLETON, Rachelle S
• PATEL, Kashyap
• PULLEN, Susan M
• HICKS, Kevin O
• SYDDALL, Sophie P
• ATWELL, Graham J

Titel

Mechanism of Action and Preclinical Antitumor Activity of the Novel Hypoxia-Activated DNA Cross-Linking Agent PR-104

Ist Teil von

• Clinical cancer research, 2007-07, Vol.13 (13), p.3922-3932

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.