Abstract
Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, and metastatic cancer phenotype. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose of this study is to characterize the antitumor activity of TH-302 and investigate its selective targeting of the hypoxic cells in human tumor xenograft models. Antitumor efficacy was assessed by tumor growth kinetics or by clonogenic survival of isolated cells after tumor excision. Hypoxic fractions (HF) were determined by immunohistochemistry and morphometrics of pimonidazole staining. Tumor hypoxia levels were manipulated by exposing animals to different oxygen concentration breathing conditions. The localization and kinetics of TH-302 induced DNA damage was determined by γH2AX immunohistochemistry. TH-302 antitumor activity was dose-dependent and correlated with total drug exposure. Correlation was found between antitumor activity and tumor HF across 11 xenograft models. Tumor-bearing animals breathing 95% O(2) exhibited attenuated TH-302 efficacy, with whereas those breathing 10% O(2) exhibited enhanced TH-302 efficacy, both compared with air (21% O(2)) breathing. TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction. TH-302 induced DNA damage as measured by γH2AX was initially only present in the hypoxic regions and then radiated to the entire tumor in a time-dependent manner, consistent with TH-302 having a "bystander effect." The results show that TH-302 has broad antitumor activity and selectively targets hypoxic tumor tissues.
Highlights
The existence of hypoxic regions is a common feature of tumors [1, 2]
Correlation was found between antitumor activity and tumor hypoxic fraction (HF) across 11 xenograft models
TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction
Summary
The existence of hypoxic regions is a common feature of tumors [1, 2]. Tumor hypoxia has been characterized clinically by a variety of different techniques, including polarographic needle-based electrodes, magnetic resonance and positron emission imaging based approaches [3], immunohistochemistry of tumor biopsies using exogenous (e.g., pimonidazole) or endogenous (e.g., CA-IX) hypoxia biomarkers [4], microRNA biomarkers [5], and circulating protein [6]. Authors' Affiliation: Threshold Pharmaceuticals, South San Francisco, California have been shown in numerous studies to correlate directly with poor clinical prognosis [7] The basis for this correlation between tumor hypoxia and prognosis has been ascribed to both therapeutic treatment failure [8,9,10] and hypoxia-induced prometastatic potential [11,12,13]. The development of hypoxia-targeted therapies has included bioreductive prodrugs, HIF-1 targeting, and genetic engineering of anaerobic bacteria [16,17,18] Among these approaches, hypoxia-activated prodrugs (HAPs) are especially promising, because they act via a mechanism involving activation of a nontoxic prodrug selectively in the hypoxic regions of tumors. Design criteria for an optimized HAP include pharmacokinetic properties to ensure adequate tumor delivery and penetration; stability to oxygen concentration-independent activating or inactivating reductases; high hypoxia selectivity with activation only in severely hypoxic tumor tissues and not moderately hypoxic normal tissues; Clin Cancer Res; 18(3) February 1, 2012
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