There are reports of promising correlations between patient response to radiotherapy and laboratory measurements of tumor radiosensitivity, fibroblast radiosensitivity, tumor proliferation, and tumor oxygenation status. These all need to be substantiated in large clinical studies. The development of rapid, reliable assays, in particular for determining intrinsic radiosensitivity, would greatly facilitate this work. If the results illustrated in the figures in the chapter can be combined and shown to be feasible on a routine clinical basis, then radiobiologists would be able to provide radiotherapists with a useful aid for the individualization of patient treatment. 162 refs., 6 figs., 6 tabs.
The development of a hospital-based proton-beam therapy system at Loma Linda University Medical Center is one step of a historical trend toward more precise radiation therapy. It exploits available technology and, in doing so, may point the way toward other, similar facilities; it is hoped that it may also point the way to true selective cell irradiation. In its present form it offers patients an opportunity for effective cancer control with reduced side effects. As an instrument of precision, it allows for physical, radiobiological, and clinical investigations not previously attainable and is, therefore, intended as a worldwide resource as well as a treatment center. As research accumulates and results are published, a better-defined role for proton-beam radiation therapy is expected to become apparent and further exploitation of protons most likely will be undertaken. The Loma Linda facility, then, represents not so much a culmination as a beginning. 43 refs., 10 figs.
Cellular radiobiology is undergoing a renaissance. The renaissance provides the impetus for change in the content of graduate courses in basic cellular radiobiology, and especially those designed for residents in radiation therapy. Emphasis on radiation physics should be reduced to a bare minimum; emphasis on the roles of biochemistry, chemistry, molecular biology, molecular genetics, and so forth in the cellular radiation response must be accentuated. Improvements in radiation therapy should follow a major shift in research emphasis to the identification of enzymes involved in cellular recovery. Theoretically, it is possible to change a survival curve by modulating or inhibiting the enzymatic processes involved in the amelioration of radiation damage to DNA. Split-dose recovery at the cellular level would be eliminated. Effective clinical utilization of specific enzyme inhibitors would increase the fiscal and logistic advantages of `conventional` therapy with sparsely ionizing radiations. 59 refs., 10 figs., 1 tab.
Publisher Summary This chapter discusses the early development of ionizing radiation damage in chromosomes. Ionizing radiations are among the most potent of clastogens, apart from being mutagenic and oncogenic. Gross structural changes—such as translocations, inversions, and deletions—appear to constitute the principal genetic alterations that underlie the malignant transformation of cells, whereas dominantly acting point mutations involving single base changes in oncogenes appear to be of minor importance by comparison. Ionizing radiation is extremely inefficient in producing point mutations involving single base changes in mammalian cells. Ionizing radiations produce a wide spectrum of lesions, many of which are known to be produced in numbers exceeding aberration yields. In addition to permanent heritable changes in surviving germ cells leading to harmful effects in future generations, ionizing radiations can lead to cell reproductive death. This cell-killing process also appears to result largely from the production of certain kinds of gross chromosomal aberrations. There have been successful attempts to sequence stretches of DNA that span break points of spontaneous chromosomal exchange-type aberrations and large intragenic deletions within endogenous genes.
Understanding the systematic and quantitative correlation between the physical events of energy deposition by ionizing radiation and the ensuing chemical and biochemical processes leading to DNA damage is one of the goals in radiation research. Significant progress has been made toward achieving the stated goal by using theoretical modeling techniques. These techniques are strongly dependent on computer simulation procedures. A review of such techniques with details of various stages of simulation development, including a comparison with available experimental data, is presented in this article.
Publisher Summary This chapter discusses the chemical consequences of radiation damage to DNA. Irradiation of DNA causes ionizations in all parts of the DNA molecule, namely, the bases, the sugar-phosphate moiety, and any closely bound water; in addition, bound proteins are also ionized. Even though ionizations occur throughout the DNA molecules, initial radicals have been observed only on the DNA bases in low-temperature ESR studies of moist DNA. Radiation damage to DNA occurs in a number of ways, which, are classified as either direct or indirect. The direct effect corresponds to direct ionization of the DNA resulting in the formation of radical cations and radical anions on the DNA itself. The indirect effect corresponds to energy deposition in the surrounding phase followed by attack by radicals from this phase. However, in complex systems such as the cell, damage may also be caused by irradiation of molecules bound to the DNA that transfer positive holes and/or electrons to the DNA strands or later react by cross-linking or hydrogen abstraction. The quasi-direct effect refers to a third process, where ionizations from irradiation result in holes and dry electrons in biomolecular species and hydration water very near the DNA. These then undergo fast transfer to the DNA to form ion radicals on the DNA itself. The indirect effect produces many of the same radicals and diamagnetic products as the direct and quasi-direct effects.
Publisher Summary This chapter discusses new approaches to investigate the role of nuclear and chromatin structure in the effects of ionizing radiation on mammalian cells. The nucleus of eukaryotic cells is the critical organelle in which interactions with ionizing radiation result in reproductive cell death. The first level of higher-order organization of DNA in chromatin is the nucleosome. Each nucleosome contains two molecules each of the four core histones that form a disk around which is wrapped ∼ 146 base pairs (bp) of DNA. Each nucleosome is separated from its neighbor by approximately 54 bp of “linker” DNA making the nucleosome repeat unit equal to ∼ 200 bp. Packaging of DNA into nucleosomes results in a fiber of approximately 11 nm in diameter. In the next level of organization, polynucleosomes are packaged into a solenoidal array of highly condensed DNA, partly because of the interaction of histone HI with the internucleosomal or “linker” DNA and nucleosome core particles. The chapter presents a study wherein effects of radiation on nucleoid sedimentation behavior were studied with two approaches: first, alterations in the ethidium bromide response were studied as a function of dose; second, alterations in the sedimentation distance were investigated. The sedimentation technique can detect changes in nucleoids induced by heat shock or by radiation with great sensitivity. However, the interpretation of what these changes mean in terms of DNA supercoiling is compromised by the absence of independent nucleoid sedimentation and varying amounts of protein co-sedimenting with the nucleoid.
Publisher Summary This chapter presents data that highlight the relative insensitivity of well-established mammalian mutation systems. While human cell systems have particular relevance in the study of radiation effects, the use of animal tissues remains important for experimental work. An overall increase in sensitivity to mutation can be achieved, in principle, by destroying the ability of cells to repair radiation damage. Alternatively, sensitivity to mutation can also be enhanced by an increase in target size of the genetic material. The use of recombinant DNA shuttle vectors, as distinct from integrating vectors, has been a favored means of studying mutation in mammalian cells in recent years because of the rapidity and precision of the analytical methods, which include the transfer of naked DNA molecules that carry small target genes into cells. Unfortunately, this protocol gives rise to considerable damage to the DNA. Ionizing radiations induce a variety of mutation types, from monogenic mutations to visible chromosomal rearrangements.
Publisher Summary This chapter discusses two types of dose-time-response models—descriptive models and mechanistic models. The value of a mechanistic model lies in its ability to organize a complex set of hypotheses into a unified framework and to allow tests of submodels within that framework. The most important human data on the carcinogenic effects of radiation exposure come from the Japanese atomic bomb survivors. The dose-response function for leukemia induction in the atomic bomb survivor data has both linear and quadratic components, with a “crossover dose”—that is, the dose at which linear and quadratic components contribute equally. As a group, the nonleukemias are characterized by generally linear dose-response relations. The chapter discusses the major concepts in radiobiology that play important roles in determining the emergence of a radiation-induced malignant cell and the subsequent expression of a tumor. Any dose-response relationship for cancer that ignores gender, age, and time effects is a serious oversimplification.
