Combined Effect of Ionizing Radiation and Alkylating Agents on Cancer Induction

摘要

References(55) Cited-By(2) Human beings are exposed to numerous natural and man-made agents that are potentially carcinogenic. Therefore, cancer risk by ionizing radiation (IR) should be assessed as a result of combined exposures with other agents. These agents include genotoxic and non-genotoxic chemical carcinogens such as, tobacco, hormones, viruses, metals etc. Carcinogenesis is a multi-step process that accumulates several genetic and epigenetic changes of oncogenes and tumor suppressor genes. For agents having similar biological function and affecting the same step of carcinogenesis, additivity is generally expected, while for agents acting at different rate-limiting step, combined exposure is expected to be deviated from additivity. Conceptually, carcinogens are classified as initiator and promoter. IR could function at several steps as initiator, promoter or both. In order to predict the mode of combined action of IR with other agents, the sequence and time interval of the exposures, the dose, and the type of exposure (acute or chronic) are the critical factors. In this review, we focus on the combined effect of IR and alkylating agents. The data in the literatures and in our laboratory on mouse thymic lymphomas indicate that combined effect of these two genotoxic agents is synergistic, additive or antagonistic, depending on the dose and the sequence. Mechanistic approach determining frequency and spectrum of cancer-related genes and loss of heterozygosity (LOH) shows that role of IR differs in combined exposures depending on the dose. At low dose range, in general, the combined effect may not deviate from additivity. More information on the mode and the mechanism of low-level exposures, which occasionally encountered in environmental and occupational situation, are required for reaching a unifying concept.