Reduction In Oxygen Enhancement Ratio Research Articles

High-LET Ion Radiolysis of Water: Oxygen Production in Tracks

It is known that molecular oxygen is a product of the radiolysis of water with high-linear energy transfer (LET) radiation, a result that is of particular significance in radiobiology and of practical relevance in radiotherapy. In fact, it has been suggested that the radiolytic formation of an oxygenated microenvironment around the tracks of high-LET heavy ions is an important factor in their enhanced biological efficiency in the sense that this may be due to an "oxygen effect" by O(2) produced by these ions in situ. Using Monte Carlo track simulations of pure, deaerated water radiolysis by 4.8 MeV (4)He(2+) (LET approximately 94 keV/microm) and 24 MeV (12)C(6+) (LET approximately 490 keV/microm) ions, including the mechanism of multiple ionization of water, we have calculated the yields and concentrations of O(2) in the tracks of these irradiating ions as a function of time between approximately 10(-12) and 10(-5) s at 25 and 37 degrees C. The track oxygen concentrations obtained compare very well with O(2) concentrations estimated from the "effective" amounts of oxygen that are needed to produce the observed reduction in oxygen enhancement ratio (OER) with LET (assuming this decrease is attributable to the sole radiolytic formation of O(2) in the tracks). For example, for 24 MeV (12)C(6+) ions, the initial track concentration of O(2) is estimated to be more than three orders of magnitude higher than the oxygen levels present in normally oxygenated and hypoxic tumor regions as well as in normal human cells. Such results, which largely plead in favor of the "oxygen in the heavy-ion track" hypothesis, could explain at least in part the greater efficiency of high-LET radiation for cell inactivation (at equal radiation dose).

Resistance of hypoxic cells to ionizing radiation is influenced by homologous recombination status

To determine the role of DNA repair in hypoxic radioresistance. Chinese hamster cell lines with mutations in homologous recombination (XRCC2, XRCC3, BRAC2, RAD51C) or nonhomologous end-joining (DNA-PKcs) genes were irradiated under normoxic (20% oxygen) and hypoxic (<0.1% oxygen) conditions, and the oxygen enhancement ratio (OER) was calculated. In addition, Fanconi anemia fibroblasts (complementation groups C and G) were compared with fibroblasts from nonsyndrome patients. RAD51 foci were studied using immunofluorescence. All hamster cell lines deficient in homologous recombination showed a decrease in OER (1.5-2.0 vs. 2.6-3.0 for wild-types). In contrast, the OER for the DNA-PKcs-deficient line was comparable to wild-type controls. The two Fanconi anemia cell strains also showed a significant reduction in OER. The OER for RAD51 foci formation at late times after irradiation was considerably lower than that for survival in wild-type cells. Homologous recombination plays an important role in determining hypoxic cell radiosensitivity. Lower OERs have also been reported in cells deficient in XPF and ERCC1, which, similar to homologous recombination genes, are known to play a role in cross-link repair. Because Fanconi anemia cells are also sensitive to cross-linking agents, this strengthens the notion that the capacity to repair cross-links determines hypoxic radiosensitivity.

Oxygen as a Product of Water Radiolysis in High-LET Tracks. II. Radiobiological Implications

Consideration is given to the possibility that molecular oxygen generated in the tracks of energetic heavy ions is responsible for the reduction in oxygen enhancement ratio (OER) with increasing linear energy transfer (LET) observed for the loss of reproductive capacity caused by radiation in many cellular organisms. Yields of oxygen derived from experiments (Part I of this paper) are applied to the observations of Alper and Bryant (Int. J. Radiat. Biol. 26, 203-218, 1974) on the relationship of OER to LET for two organisms, Chlamydomonas reinhardii and Shigella flexneri, using a simple diffusion kinetic model for radiobiological action which takes account of the diffusion of oxygen after its formation. The results of these calculations show that the model accounts well for the shape of the OER vs LET relationship and that the initial G value of lesions GL for low-LET radiation needs to be of the

Neutron Irradiation of Bacteria in the Presence and Absence of Secondary Charged-Particle Equilibrium

The survival rate of Shigella flexneri has been measured for irradiation with 7-MeV neutrons in the presence and absence of secondary charged-particle equilibrium. The data were analyzed to assess the separate response of the cells to the knock-on proton and ..cap alpha..-particle plus heavy-recoil components. A detailed consideration of the frequency of ..cap alpha..-particle and heavy-recoil traversals of the cell has been made to explain our results, and in addition we have applied this approach to analyze the earlier results obtained with mammalian cells. We conclude that of the secondary charged-particles produced by the Hammersmith neutron beam, the highest LET particles, the heavy-recoil nuclei, contribute a minor proportion of damage to bacteria but form a major contribution of damage in mammalian cells. The reduction in oxygen enhancement ratio (OER) with neutrons compared with low LET radiation for mammalian cells is due almost entirely to the influence of the heavy recoils and the contribution of the ..cap alpha..-particle and knock-on protons to the reduction of the OER is relatively minor. For Shigella flexneri the ..cap alpha.. particles and heavy recoils make approximately equal contributions to the reduction in OER.

Reduction in oxygen enhancement ratio with increase in LET: tests of two hypotheses.

SummaryMeasurements of o.e.r. and of the ‘oxygen constant’ K may be used to calculate effective concentrations of oxygen engendered in the tracks of ionizing particles, if it is correct to invoke that phenomenon to account for decreasing o.e.r. with increasing LET. Effective O2 concentrations calculated from results with Shigella flexneri and Chlamydomonas reinhardii are in good agreement, although the radiobiological responses of those organisms are widely different in several respects. The relevant oxygen concentrations so calculated account plausibly also for variations of o.e.r. with radiation quality in mammalian cells. Tests have also been formulated to examine the validity of the ‘interacting-radicals’ hypothesis of Alper (1956) and Howard-Flanders (1958) by the use of data on changes in o.e.r. and biological effectiveness with radiation quality. These tests have failed to support the latter hypothesis.

The Repair of DNA Single-Strand Breaks in E. coli K-12 X-Irradiated in the Presence or Absence of Oxygen; The Influence of Repair on Cell Survival

(W3110) after X irradiation in the presence and absence of oxygen. Upon completion in buffer of a very fast repair process (Type I) there are three times as many breaks remaining after irradiation in the presence as compared with the absence of oxygen. These breaks are then rapidly repaired in buffer by the Type II system; a process that is deficient in strains carrying the polAl mutation (an amber mutation in the structural gene for DNA polymerase I). After low doses of x rays, the Type II system can repair all of the breaks presented to it. Beyond a threshold dose it repairs a constant proportion (-90%) of the breaks presented to it whether or not oxygen is present during irradiation. Consistent with the apparent insensitivity of the Type II repair process to the presence of oxygen during irradiation, otherwise isogenic pol+ and pol- derivatives were found to have the same oxygen enhancement ratio (OER) for cell survival. After Type II repair is complete, some of the remaining breaks can be repaired by the growth-medium-dependent Type III system. This process can repair only about 2 additional breaks per single-strand genome in this strain, whether irradiation is in the presence or absence of oxygen. Thus, as far as the repair of DNA single-strand breaks is concerned, neither the Type II nor the Type III repair system shows any specificity for breaks produced in the presence or absence of oxygen. OER values were determined for the recA and recB mutants which are deficient in Type III repair. While the recB derivative showed only a slight reduction in OER, the recA derivative had an OER of about 2.0 compared with about 3.4 for the rec+ parental strain. Since the recA mutation would affect Type III repair to the same extent whether the cells were x-irradiated in the presence or absence of oxygen, the reduced OER for the recA strain probably reflects the additional involvement of the recA gene product in the repair of some other lesion, possibly based damage, that is affected by the presence of

The effect of anoxia on the response of haemopoietic colony-forming units in different proliferative states to rays or D-T neutrons.

Abstract The spleen colony assay technique was used to measure the oxygen enhancement ratio (OER) for the stem cells in mouse bone marrow, irradiated with γ rays or a collimated 14 MeV neutron beam. The reduction in OER with neutrons compared with low LET radiation, found in most biological systems studied, was also observed in the present experiments. However, a difference was found between the γ-ray OER for steady-state marrow (1·77 ± 0·12) and that for regenerating marrow (2·51 ± 0·08), which resulted in a larger gain factor for the latter (1·87 ± 0·13) than the former (1·37±0·17). The differences are considered to result from radiation effects on the complex processes involved in the differentiation and proliferation of these cells, rather than from differences in oxygen tension. The implications of the results for radiotherapy are discussed.

The Role of Dose Rate, Irradiation Technique, and LET in Determining Radiosensitivities at Low Oxygen Concentrations

As oxygen concentration increases from zero, the rate of increase in radiosensitivity may be measured by K in the expression r = (m[O] + K)/([O] + K), r being the sensitivity relative to that in complete anoxia, [O] the oxygen concentration, and m and K constants. The value of K depends on the dose rate and the irradiation technique. For organisms in suspension, K was greater at high than at low dose rates: and, at high dose rates, it was greater for organisms in aqueous suspension than for those exposed directly to the ambient gas. Changes in the value of K are much more dependent on those variables than on the LET of the radiation. Values of K were compared for 250-kVp X-rays and fast neutrons from the Medical Research Council Cyclotron. The value of K was higher with the radiation of higher LET, supporting the hypothesis that reduction in oxygen enhancement ratio with increasing LET may be ascribed to the formation of oxygen in the irradiated material in the tracks of heavily ionizing particles.