Hypoxia-Activated Prodrugs (HAPs) are prodrugs 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,[1] 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 of aggressive cancers by promoting genetic instability and accelerating the accumulation of mutations that can ultimately give rise to drug resistance.[2][3]
There are several companies developing HAPs: Novacea, Inc. (acquired by Transcept/Paratek pharmaceuticals[4][5]), Proacta Inc. (now defunct[citation needed]) and Threshold Pharmaceuticals, Inc. These companies are involved in developing the following drug candidates: AQ4N (Novacea), PR-104 (Proacta) and TH-302 (evofosfamide) and TH-4000 (tarloxotinib)[6] (Threshold Pharmaceuticals).
References
edit- ^ Minchinton, Andrew I.; Tannock, Ian F. (August 2006). "Drug penetration in solid tumours". Nature Reviews Cancer. 6 (8): 583–592. doi:10.1038/nrc1893. PMID 16862189. S2CID 42818461.
- ^ Gillies, Robert J.; Gatenby, Robert A. (3 April 2007). "Hypoxia and adaptive landscapes in the evolution of carcinogenesis". Cancer and Metastasis Reviews. 26 (2): 311–317. doi:10.1007/s10555-007-9065-z. PMID 17404691. S2CID 2276912.
- ^ Sullivan, Richard; Graham, Charles H. (26 April 2007). "Hypoxia-driven selection of the metastatic phenotype". Cancer and Metastasis Reviews. 26 (2): 319–331. doi:10.1007/s10555-007-9062-2. PMID 17458507. S2CID 13457619.
- ^ "Novacea to be acquired by Transcept Pharmaceuticals". Reuters. 2008-09-02. Retrieved 2016-03-22.
- ^ Pharmaceuticals, Paratek (30 October 2014). "Paratek Pharmaceuticals Completes Merger With Transcept Pharmaceuticals". GlobeNewswire News Room (Press release). Retrieved 2016-03-22.
- ^ "Tarloxotinib bromide* (TH-4000): Combining molecular targeting and hypoxia targeting in a single drug candidate". Threshold Pharmaceuticals. Archived from the original on 5 April 2016. Retrieved 24 March 2016.