[Some instructions for radiation protection in dental radiology].
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The ability to protect parenchymal hepatocytes from ionizing radiation damage with S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR-2721) was investigated. The clonogenic survival of irradiated hepatocytes was determined with an in vivo transplantation assay system. Injection of WR-2721 (400 mg/kg) immediately after irradiation was without protective effect. In contrast, an intraperitoneal (IP) injection of WR-2721 30 min prior to 60Co irradiation resulted in a significant protection of parenchymal hepatocytes. The mean lethal dose (Do) and extrapolation number (n) of the survival curve for unprotected hepatocytes as 2.9 Gy and 1.8, respectively. The Do and n values for hepatocytes protected with WR-2721 were 5.7 Gy and 1.8, respectively. Thus, WR-2721 at a concentration of 400 mg/kg acted as a dose modifying agent with a dose modifying factor of approximately 2.0. Decreasing the concentration of WR-2721 to 200 mg/kg did not significantly reduce the radioprotective effectiveness of the drug. However, at concentrations less than 200 mg/kg, the radioprotective effect decreased in a dose-response manner with a concentration of 150 mg/kg providing 50% of the maximum effect observed.
The gastrointestinal cell renewal system is sensitive to injury by ionizing radiation. Natural prostaglandins (PGs) and their analogs have been shown to protect intestinal clonogenic cells (stem cells) in vivo from radiation injury. To further investigate structure and activity relationship in PGs as radiation protectors, studies were done with four E-series PGs: E1, E2, 16,16-dimethyl (dm) PGE2, and 15-deoxy, 16-methyl, 16-hydroxy PGE1 (misoprostol). No protection was seen with PGE1 at doses ranging from 1-100 ug/mouse given from 15 min to 3 hrs before 15.0 Gy137Cs. In contrast, the other three E-series PGs increased intestinal clonogenic cell survival when given 15 min before irradiation. The optimum pre-irradiation time of PG administration was 1 hr for PGE2 and 16,16-dm PGE2 and 2 hrs for misoprostol. The degree of maximum radiation protection was markedly different among the four PGs. PGE2 increased survival to 200% of control values and 16,16-dm PGE2 increased survival to about 400% of controls. The greatest radioprotection was seen with misoprostol, which increased survival to 600% of control. These results suggest that molecular alterations in the side chains of PGs change the efficiency of PG-induced radiation protection. The highest protection to date has been observed with misoprostol. This important finding warrants clinical investigation in patients subjected to radiotherapy.
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Ionizing radiation is extremely harmful for human cells, and DNA double-strand breaks (DSBs) are considered to be the main cytotoxic lesions induced. Improper processing of DSBs contributes to tumorigenesis, and mutations in DSB response genes underlie several inherited disorders characterized by cancer predisposition. Here, we performed a comprehensive screen for genes that protect animal cells against ionizing radiation. A total of 45 C. elegans genes were identified in a genome-wide RNA interference screen for increased sensitivity to ionizing radiation in germ cells. These genes include orthologs of well-known human cancer predisposition genes as well as novel genes, including human disease genes not previously linked to defective DNA-damage responses. Knockdown of eleven genes also impaired radiation-induced cell-cycle arrest, and seven genes were essential for apoptosis upon exposure to irradiation. The gene set was further clustered on the basis of increased sensitivity to DNA-damaging cancer drugs cisplatin and camptothecin. Almost all genes are conserved across animal phylogeny, and their relevance for humans was directly demonstrated by showing that their knockdown in human cells results in radiation sensitivity, indicating that this set of genes is important for future cancer profiling and drug development.
The opportunity to write a historical review of the field of radiation biology allows for the viewing of the development and maturity of a field of study, thereby being able to provide the appropriate context for the earlier years of research and its findings. The pioneering work of Muller, Sax, and McClintock, and many others, has stood the test of time. The idea that x-rays could damage the genetic material and result in interactions that could lead to gene mutations and a range of chromosomal alterations is now interpretable in terms of induced DNA damage and errors of DNA repair. The expanded idea that such genetic alterations can be induced by DNA damage that is produced by one or two tracks of ionizing radiation remains the mainstay of radiation biology. The impact of the more recent molecular approaches to unraveling the mechanism behind this simple concept has confirmed this fundamental observation. The remarkable advances have allowed for a fairly complete understanding of the specific types of DNA damage induced by ionizing radiations and the pivotal role played by the errors of repair of double-strand breaks. Given our considerably enhanced knowledge of the details of the DNA repair processes involved, misrepair is a very unlikely event. The role of potential confounders of the concept of dose-response (e.g., bystander effects, genomic instability, and adaptive responses) is taking on a growing importance to the field. The evolving need is to begin to consider mechanistically-based dose-response models for cancer risk such that any potential impact of confounders on the response at low, environmental doses can be assessed. Thus, radiation biology research has always had a focus on how best to protect human health from radiation exposures and will continue to do so.