Biol. Pharm. Bull. 29(12) 2335—2342 (2006)

As the molecular mechanisms behind tumor hypoxia have now been delineated, the important conclusion of the radiation oncologist Dr. Okuyama that “hypoxic milieu as the primary cancer environment” needs to be reexamined for its impact on current cancer diagnosis and treatment. It is apparent that, although hypoxic tumor cells cannot live without oxygen and nutrients, aggressive tumor cells isolated far from blood still survive in spite of a low supply of these. Because of their low radiosensitivity these hypoxic tumor cells are recognized as a potential problem in radiotherapy and a predictor of poor prognosis and recurrence. Accordingly, development of hypoxic cell radiosnesitizers to enhance the radiosensitivity of tumor hypoxic cells has been a goal of medicinal chemists. However, to date there are no clinicallyavailable drugs with the exception of nimorazole, used locally in Denmark. In the traditional paradigm of radiobiology, the design of radiosensitizers focused on the development of oxygen mimics that could partially compensate for the low oxygen environment to increase radiation-induced DNA damage. However, modern “molecular target-based hypoxic cell radiosensitizers” designed on the basis of the survival strategy of tumor cells in the tumor microenvironment would appear to be more promising candidates. In this review, we describe the current status of drug discovery research in radiotherapeutics. We include our own recent efforts on the development of molecular target-based hypoxic cell radiosensitizers and hypoxic cytotoxins that inhibit hypoxia adaptation mechanisms, including angiogenesis and metastasis, and discuss the prospects for future progress in this area.