Hypoxia-Activated Prodrugs (HAPs) are

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

s that target regions of tumor hypoxia within tumor cells. HAPs may offer the potential, alone and in combination with conventional chemotherapy, of improving cancer therapy. It is believed that tumor hypoxia contributes significantly to treatment failure and relapse among cancer patients because cells in the hypoxic zones of solid tumors resist traditional chemotherapy for at least two reasons: first, most antitumor agents cannot penetrate beyond 50-100 micrometers from capillaries, thereby never reaching those cells in the hypoxic regions. Secondly, the lower nutrient and oxygen supply to cells in the hypoxic zones of tumors cause them to divide more slowly than their well oxygenated counterparts, so hypoxic tumor cells exhibit greater resistance to chemotherapies and radiation which target rapidly dividing cells or require oxygen for efficacy. Hypoxia also contributes to the invasive and metastatic

phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

of aggressive cancers by promoting genetic instability and accelerating the accumulation of mutations that can ultimately give rise to drug resistance. There are several companies developing HAPs: Novacea, Inc. (acquired by Transcept/Paratek pharmaceuticals), Proacta Inc. (now defunct) and Threshold Pharmaceuticals, Inc. These companies are involved in developing the following drug candidates: AQ4N (Novacea),

PR-104 PR-104 is a drug from the class of hypoxia-activated prodrugs (HAPs), which is being researched as a potential anti-cancer therapeutic agent. It is a phosphate ester “pre-prodrug” that is rapidly converted to the HAP PR-104A in the body. PR-10 ...

(Proacta) and TH-302 (evofosfamide) and TH-4000 (tarloxotinib) (Threshold Pharmaceuticals).

References

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