Radiation Biology And Cancer

The biological effect of radiation on living cells tends to vary and depends on dose. It is well known that radiation is known to cause cancer, but in clinical practice, radiotherapy is an accepted form of cancer treatment. Injured or damaged cells may self-repair, die, or be involved in a misrepair process (see discussion later). High-radiation doses tend to kill cells, while low doses tend to damage or alter the genetic code (DNA) of irradiated cells. High-radiation doses can kill so many cells that tissues and organs are damaged immediately and tend to initiate a rapid body response, often called "acute radiation syndrome." High-radiation dose manifests itself early. This was evident in many of the atomic bomb survivors in 1945 and in the emergency workers who responded to the 1986 Chernobyl nuclear power plant accident (Sali et al., 1996). Low doses of radiation over long periods may not cause immediate problems in body organs, but effects may occur at the cellular level. Genetic effects and the development of cancer are the primary health concerns attributed to radiation exposure (see below). The likelihood of cancer occurring after radiation exposure is about five times greater than a genetic effect (see review by Abrahamse, 2003).

Genetic effects are the result of a mutation produced in the reproductive cells of an exposed individual that are passed on to his or her offspring. Although these effects are widely suggested to appear in the exposed person's direct offspring or several generations later (depending on whether the altered genes are dominant or recessive), radiation-induced genetic effects are often observed in laboratory animals (given very high doses of radiation). However, according to the U.S. Nuclear Regulatory Commission (http ://environment.about.com), no statistically significant increase in genetic effects has been observed among the children born to atomic bomb survivors from Hiroshima and Nagasaki.

The association between radiation exposure and the development of cancer is mostly based on populations exposed to relatively high levels of ionizing radiation (e.g., Japanese atomic bomb survivors and recipients of selected diagnostic or therapeutic medical procedures where radiation represents the major anticancer modality in terms of successful tumor care and patient survival) (Abrahamse, 2003). Those cancers that may develop as a result of radiation exposure are indistinguishable from those that occur naturally or as a result of exposure to other chemical carcinogens. Chemical and physical hazards and lifestyle factors (e.g., smoking, alcohol consumption, and diet) contribute to many of these same diseases. Cancers associated with high-dose exposure include leukemia, breast, bladder, colon, liver, lung, esophagus, ovarian, multiple myeloma, and stomach cancers. Radiation biology focuses on the understanding of the physical, biological, and chemical mechanisms of the interaction of radiation with living matter.

In living cells, there is a steady formation of DNA lesions. A substantial number of these lesions are formed by endogenous factors that damage DNA on a continuous basis. Free-radical attack upon DNA generates a series of modified purine and pyrimidine base products (Figure 6.1). One of the widely studied product is 8-oxo-7,8-dihydroguanine (8-oxoGua). To form 8-oxoGua, a hydroxyl radical first reacts with guanine to form a C8-OH adduct radical. The loss of an electron (e-) and proton (H+) generates 8-oxoG. The C8-OH adduct radical can also be reduced by uptake

FIGURE 6.1 A wide range of oxidized and ring-fragmented nitrogen bases that are formed by endogenous reactive oxygen species or by ionizing or UV radiation. (Adapted from Dizdasoglu 2000 in Free Radicals in Chemistry, Biology, and Medicine. With permission from OICA International, Landon.)

of an electron and a proton to form 7-hydro-8-hydroxyguanine, which is subsequently converted to 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FaPy). The formation of 8-oxoGua residues in DNA leads to GC^-TA transversions unless repaired prior to DNA replication, and this may lead to point mutations (Aruoma and Halliwell 1998).

The most common damage to pyrimidines is the formation of thymine glycol (Tg), which results from attack by a hydroxyl radical to yield a 5-hydroxy-6-yl radical. In the absence of oxygen, loss of an electron followed by uptake of water and loss of a proton generates thymine glycol. In the presence of oxygen, uptake of oxygen at position 6 first yields a 5-hydroxy-6-peroxyl radical, which is converted to thymine glycol through loss of a proton and superoxide anion and reaction with water. Indeed 5-methylcytosine (5-meC) can also be converted to thymine glycol by ionizing radiation under aerobic conditions or H2O2, and thus may be an additional source of mutations in organisms that utilize 5-meC to regulate gene expression. The level of the modified bases in vivo can depend on oxidative DNA insult and can be reflective of an involvement of different repair mechanism(s). Increased levels of modified DNA bases may contribute to the genetic instability and metastatic potential of tumor cells in fully developed cancer. A direct correlation between 8-oxoGua formation and carcinogenesis in vivo as well as the induction of mutagenesis in hotspot codons of the human p53 and Ha-ras genes are widely suggested.

The reader is referred to articles in volume 531 (Issue 1-2) of the journal Mutation Research for views on oxidative DNA damage and its repair, which is important for understanding the importance of oxidative stress in the development of cancer. These articles include some salient observations, including the fact that cancer patients show signs of extensive granulocyte activation with a release of ROS and show increases in the levels of 8-isoprostane, one of the biomarkers of oxidative stress. Tumors may stimulate the defense systems of the body so that they react against the tumor to produce cytokines (e.g., TNF, which is known to increase oxidative DNA damage of CD 34+ cells). It is also possible that a pro-oxidant environment is characteristic of advanced stages of cancer and that oxidative stress is a result of the disease development.

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