Cellular, molecular, and carcinogenic effects of radiation

(1) The biologic effects of ionizing radiation at the cellular and molecular levels differ from those of many chemical agents. Radiation is a classic genotoxic agent. The important DNA lesion with respect to its cytotoxic and mutagenic effects appears to be the DNA double strand break, whereas chemotherapeutic alkylating agents induce primarily base damage from adduct formation and cross-linking. Radiation-induced mutations result primarily from large-scale structural changes in DNA as a result of mechanisms such as chromosomal deletions, rearrangements, and homologous recombination, rather than point mutation as generally observed with alkylating agents. Finally, radiation is highly cytotoxic; a significantly increased frequency of specific gene mutations is usually observed only following doses that produce significant cell killing. (2) Radiation may not be a very potent inducer of second malignant tumors, at least in most cases. This prediction is derived from the localized nature of the exposure during clinical radiotherapy, in which the dose to normal tissues is minimized, and from the fact that radiation tends to be cytotoxic rather than mutagenic. The very high doses employed in curative radiotherapy may thus kill potentially transformed cells in the field. An exception to this general prediction may be Hodgkin's disease, in which a relatively large volume of tissue is treated with lower total radiation doses. (3) We have a firm scientific basis on which to predict the carcinogenic effects of radiation at many tissue sites, owing to extensive quantitative epidemiologic data in human populations. Unlike for chemical agents, radiation can be easily detected, and the absorbed dose to critical tissues is precisely measured. Thus, we know about the sensitivity of many target tissues to radiation-induced cancer. (4) A number of factors can modify the carcinogenic effects of radiation. It is likely that important interactive effects will occur between radiation and chemotherapeutic alkylating agents, which may depend upon the timing and order of the treatments as well as the particular agent(s) employed. (5) Genetic predisposition to radiation-induced cancer may be a confounding factor in the prediction of its effects in any given individual.