Abstract
The presence of “hypoxic” tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.
Highlights
The Problem of Tumour HypoxiaHypoxia is a common phenomenon in clinical solid tumours [1] and in rodent laboratory models of transplantedCitation: Denny, W.A
A second approach to hypoxia-activated prodrugs is the use of a variety of different nitroheterocyclic nitroheterocyclic or or nitrophenyl nitrophenyl “triggers”, “triggers”, where where the the electron electron release release on on reduction reduction of the nitro thethe linker to release a cytotoxic effector
Ge et al [24] reported the 4-nitrobenzyl-triggered hypoxiaactivated nitrosourea prodrug NBGNU (11), which was designed to induce DNA interstrand crosslinks following reduction, by inhibiting O6-alkylguanine-DNA alkyltransferase, an enzyme which has the ability to suppress the chemotherapeutic effect of chloroethylnitrosoureas by removing drug-induced alkyl groups from the O6-site of guanine
Summary
Hypoxia (defined as a free oxygen concentration of
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