Abstract
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Highlights
Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs
Bioreductive prodrugs can be designed for selective activation under low oxygen conditions typical of many solid tumors
We have shown that the diflavin oxidoreductases, such as cytochrome P450 oxidoreductase (POR), activate bioreductive prodrugs in human cell cultures; the frequency of expression in human cancers appears to be low and generally does not overlap with biological markers of hypoxia such as carbonic anhydrase IX[20]
Summary
Hypoxia-activated prodrugs are deactivated or masked cytotoxins that undergo biotransformation following reductive metabolism by endogenous human cellular oxidoreductases This process is usually inhibited by molecular oxygen, thereby imparting specificity for the hypoxic tumor microenvironment. One-electron oxidoreductases generate prodrug free radical species that are readily back-oxidized resulting in a futile metabolic cycle[19] This reversible step ensures prodrug activation is restricted to tissues experiencing limited oxygen availability. Two-electron reduction by certain oxidoreductases fails to generate an oxygen-sensitive radical intermediate This metabolic process is irreversible and may occur in tumors and normal tissues. Several nitroaromatic compounds have been evaluated in clinical trials, including the nitroimidazoles misonidazole, etanidazole, and nimorazole These agents were primarily designed as radiosensitizers (i.e., oxygen mimetics), and derivatives have been developed for hypoxic cell imaging using immunohistochemistry [e.g., pimonidazole, EF5 [2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] or positron emission tomography (PET; e.g., [18F]floromisonidazole, [18F]-EF5, [18F]-flortanidazole).
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