Abstract 4465: In vivo antitumor characterization of the hypoxia-activated prodrug TH-302 in a preclinical SCLC xenograft model

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.4465-4465
• Main Authors: Sun, Jessica D., Ahluwalia, Dharmendra, Liu, Qian, Wang, Yan, Hart, Charles P.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-4465

The hypoxia activated prodrug TH-302, has showed anti-tumor activity in a variety of preclinical in vivo models. In hypoxic conditions, TH-302 acts as a DNA crosslinking agent by the reductase- and oxygen concentration-dependent release of bromo-IPM. In the present study, we investigated the anti-cancer mechanisms of TH-302 in a small cell lung cancer (SCLC) xenograft model with a focus on selective effects on the hypoxic compartment and tumor vasculature. The ectopic xenograft model was set up by s.c. implantation of 5×106 H82 human SCLC cells into the flank of nude mice. When tumor size reached 500 to 700mm3, animals were randomized (5-8 mice/group) and were injected i.p. with a single dose of 150mg/kg TH-302 or vehicle. Tumors were harvested for frozen sections 24, 48 and 72 hours after TH-302 treatment. Pimonidazole, for detection of hypoxia, was administered at 60mg/kg i.p. 1 hour before sacrifice, and to assess the effect of TH-302 on tumor vascular perfusion, Hoechst 33342 was injected at 10mg/kg i.v. into the tail vein 1 min before sacrifice. Anti-CD31 antibody was utilized as a marker for the microvasculature. Morphometric analysis was conducted by point counting and with Image-Pro Plus 6.0 software. Previous studies showed that TH-302 as a single agent, exhibited efficacy in the H82 xenograft model with tumor growth inhibition at about 55%. In the current study, anti-tumor activity was evaluated by assessment of tumor necrosis after H&E staining. The necrotic fraction in the vehicle treated tumor was 7.3% and reached 17.2%, 37.9% and 34.8% after 24, 48 and 72hrs of TH-302 treatment, respectively. A significant increase of necrosis occurred from 48hrs after the treatment (p