Biochemical pharmacology of chemotherapeutic drugs used as radiation enhancers

Abstract

Radiotherapy and chemotherapy are often administered concurrently in an attempt to take advantage of postulated biochemical or molecular interactions between the two modalities. It is generally assumed that the drugs influence some mechanism of radioresistance rather than that radiation has any direct effect on the mechanisms of cell kill by chemotherapy. Many classes of drugs have been found to interact with radiation. Classic radiosensitizing agents include the halogenated pyrimidines and the nitroimidazoles; however, many conventional cytotoxic agents, such as hydroxyurea, 5-fluorouracil (5-FU) and cisplatin, also enhance cell kill by radiotherapy. Hydroxyurea has been shown to inhibit excision-repair of thymine dimers and single-strand DNA breaks induced by radiation. Exposure of cells to 5-FU following radiation produces synergistic cytotoxicity in several model systems. The precise cellular mechanisms by which 5-FU and radiotherapy interact have not been defined, although inhibition of repair of radiation-induced DNA damage has been postulated to occur. Cisplatin has also been shown to enhance the cytotoxicity of radiation in both cell culture and tumor-bearing animals, although the mechanisms of the interaction have not been defined. Hydroxyurea, 5-FU, and cisplatin also undergo a number of biochemical interactions that enhance their cytotoxic effects. Thus, a rationale exists for employing these drugs in combination with radiation. Additional studies are required to understand the mechanisms of drug-radiation interactions and to determine the optimal scheduling of these therapies.