Chemical radiosensitizers in cancer therapy

The development of effective low-LET radiation therapy for cancer has been hindered by the lack of consistent differential responses to radiation between tumor and normal tissues. One major difference between many solid tumors and the surrounding normal stroma is the presence of hypoxic foci in solid tumors due to the inadequate supply of nutritional needs as a result of the breakdown of microvasculature. Consequently, failure of conventional radiotherapy and local recurrences are in part attributed to the radioresistant hypoxic cell populations, present in the tumor. Local cure/control rates of a tumor can be increased only by an effective increase in the radiation dose. At the same time, an increase in such a dose would damage the oxic normal stroma, more than the hypoxic tumor cells. Hence, specific modification of tumor radiosensitivity by the use of chemical radiosensitizers, in combination with conventional radiotherapy, is an attractive alternative. Many clinicians and radiotherapists are skeptical about the outcome of using radiosensitizers in patients. Nevertheless, a vast amount of information is currently available regarding the first- and second-generation radiosensitizers both in murine and in human tumors. As a result, it is hoped that eventually a radiosensitizing drug would be discovered/synthesized that will overcome the drawbacks so far encountered in their use in the clinic. In this article, the development of chemical radiosensitizers since the early sixties, the basis for their selection, their mechanism(s) of action, and the results obtained with the various groups of radiosensitizers are reviewed.