Tumor hypoxia

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic tumor cells are usually resistant to radiotherapy and chemotherapy, but they can be made more susceptible to treatment by increasing the amount of oxygen in them. Bioreductive prodrugs also play a significant part in dealing with these kinds of cells: they can kill the oxygen-deficient tumor cells selectively as hypoxic cytotoxins. The study of tumors in such conditions was pioneered by Dr L. H. Gray.

It can also be a result of the high degree of cell proliferation undergone in tumor tissue, causing a higher cell density, and thus taxing the local oxygen supply.

There are several companies working to address tumor hypoxia: Novacea, Inc., Proacta Inc. and Threshold Pharmaceuticals, Inc. These companies are developing the following drug candidates: AQ4N (Novacea), PR-104 (Proacta) and TH-302 (Threshold Pharmaceuticals). These drug candidates target levels of hypoxia that are common in tumors but are rare in normal tissues. The hypoxic zones of tumors generally evade traditional chemotherapeutic agents and ultimately contribute to relapse. In the literature, hypoxia has been demonstrated to be associated with a worse prognosis, making it a determinant of cancer progression and therapeutic response . Several recent review articles summarize the current status of hypoxic cytotoxins (hypoxia activated prodrugs).

Niacinamide, the active form of vitamin B3, acts as a chemo- and radio-sensitizing agent by enhancing tumor blood flow, thereby reducing tumor hypoxia. Niacinamide also inhibits poly(ADP-ribose) polymerases (PARP-1), enzymes involved in the rejoining of DNA strand breaks induced by radiation or chemotherapy.[1].

See also

• Hypoxia

References

W. A. Denny, Prodrug strategies in cancer therapy, Eur. J. Med. Chem., 2001, 36, 577–595

Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix; M. Hockel; Canc. Res. 56: 4509, 1996.

Hypoxia in cancer: significance and impact on clinical outcome; P. Vaupel and A. Mayer; Cancer Metastasis Rev. 26: 225, 2007.

Exploiting tumor hypoxia in cancer treatment; J.M. Brown and W.R. Wilson; Nat.Rev.Canc.4,437, 2004.

Hypoxia: targeting the tumor; R.G. Boyle and S. Travess; Anticancer Agents Med. Chem. 64:281, 2006.

Targeting tumors with hypoxia-activated cytotoxins; G.O. Ahn and M. Brown; Frontiers in Bioscience 12, 3483, 2007.

Bioreductive drugs: from concept to clinic; S.R. McKeown; Clin. Oncol. (R. Coll. Radiol.) 19,427, 2007.

Hypoxia-driven selection of the metastatic phenotype; Richard Sullivan, Charles H. Graham; Cancer Metastatis Review (2007) 26:319-331