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Biomedical subjects

M R Raju

Publications and source records attributed to M R Raju.

At least 37 records · Page 2Linked to original sources
PubMed1989

Tolerance of spinal cord, lung and rectum after fractionated pions and X-rays.

The chronic and late effects of fractionated negative pi-mesons (pions) and X-rays were investigated in rat spinal cord and rectum, and in mouse lung. Range modulated pions with a 6 cm Bragg peak were used at an average dose-rate of 0.2 Gy/min. Control studies were performed with 250 kV or 300 kV X-rays. The following functional and histological endpoints were used: paralysis and white matter necrosis after spinal cord irradiation, ulceration and fibrosis of the rectum, breathing frequency and pneumonitis after lung irradiation. The presence of a large low-LET component was reflected by a significant dose-rate effect for spinal cord and lung. This resulted in RBE values smaller than unity for single doses, since the reference X-irradiations were done at high dose-rate. For small fraction sizes and short exposure times the influence of the dose-rate is insignificant. The RBE values at pion doses of 1 to 2 Gy per fraction were found to be not higher than 1.5 for all tissues studied. These values are similar compared to published data for acute effects. This is in contrast to the effects of neutrons, which in general show higher RBE's for late effects. It can be concluded from our studies that the radiobiological characteristic of pions in a spread Bragg peak are influenced by the low-LET component of the beam. Unlike with neutrons, there are no significant differences between the RBE values for late and acute effects.

Animals↗
PubMed1989

Radiobiology of ultrasoft X rays. III. Normal human fibroblasts and the significance of terminal track structure in cell inactivation.

Ultrasoft characteristic X rays from carbon (0.28 keV) are severely attenuated as they pass through biological material, causing a nonuniform distribution of dose to cell nuclei. Complications of studying ultrasoft X rays can be minimized in this context by using cells with very thin cytoplasm and nuclei (e.g., less than the attenuation length of the X rays), and which exhibit a more nearly exponential dose response to cell killing, such as normal human fibroblasts compared with V79 cells. Using this cell system, we report the relative biological effectiveness (RBE) of A1-K and C-K X rays to be near unity. Previous studies of cell inactivation by characteristic carbon X rays gave RBEs of 3 to 4, supporting the idea that localized energy depositions from secondary electrons and primary track ends represent the principal mode of biological action for other low-LET radiations. In part, the reported high RBEs result from the use of mean dose to describe energy deposited within the cell nuclei by these poorly penetrating radiations. Implicit in the use of mean dose is that cellular damage varies linearly with dose within a critical target(s), an assumption that is of questionable validity for cells that exhibit pronounced curvilinear dose responses. The simplest interpretation of the present findings is that most energy depositions caused by track-end effects are not necessarily more damaging than the sparsely ionizing component.

Cell Survival↗
PubMed1989

Radiobiology of ultrasoft X rays. IV. Flat and round-shaped hamster cells (CHO-10B, HS-23).

The results reported earlier in this series indicated that the relative biological effectiveness (RBE) of ultrasoft X rays decreases with decreasing cell thickness, approaching unity for the thinnest cells used, plateau-phase human skin fibroblasts (HSF). The possible dependence of RBE on the configuration of the cell nucleus is investigated further in this paper using two CHO cell lines that attach well and have similar intrinsic radiosensitivities to 60Co gamma rays. One of the lines forms monolayers similar to V79 cells, while the other remains more spherical during growth. We find an increasing RBE with decreasing X-ray energy for both of these cell lines, consistent with our results using V79 cells. Also consistent with our results obtained with 10T1/2 and HSF cells, we find an increasing RBE with increasing cell thickness. The possible dependence of RBE on radiosensitivity and the use of the concept of mean dose for ultrasoft X rays is discussed.

Animals↗
PubMed1988

Radiation tolerance of the rat rectum to fractionated X-rays and pi-mesons.

A 2.5 cm segment of the rectum of female F344 rats was irradiated with up to 10 fractions of X-rays or pions. Transient signs of acute proctitis were followed by chronic rectal injury starting at about 2 months. Recto-vaginal fistulas were frequently observed in animals with severe chronic injury. Two patterns of chronic injury were observed, an early type consisting of deep ulcers and fistulas, and a late type characterized by vascular injury, fibrosis and mucosal cysts. In a 4-fraction X-ray experiment, the influence of a low-residue diet was compared with a regular diet, showing no significant differences in pathology or survival. Isoeffective doses were determined for the occurrence of severe rectal injury at 250 days. Fitting the data to an LQ-model yielded an alpha/beta ratio of 13 Gy for pions, and 6.5 Gy for X-rays. Increasing the overall treatment time from 9 days to one month gave a significant rise in isoeffective doses for chronic injury. This suggests that the more delayed types of injury did not develop independently from the acute mucosal changes. The RBE of pions for rectal injury at 250 days was 1.2 for single doses, increasing to about 1.4-1.5 at a dose per fraction of 4 Gy. These values are similar to those obtained in other acute and late responding tissues.

Animals↗
PubMed1988

Late effects of fractionated pi-mesons compared to X rays on mouse lung.

Early and late delayed effects of up to 20 fractions of pions and X rays were investigated in the mouse lung. The whole thorax of female CD-1 mice was irradiated under Ethrane/O2 anesthesia. Respiration rate was measured by whole body plethysmography at biweekly to monthly intervals. With signs of irreversible respiratory distress, animals were sacrificed and their lungs evaluated histologically. In addition to the effect of fractionation, the influence of dose-rate and anesthesia was studied as well. The degree of injury for the most predominant lesions (macrophage accumulation, fibrosis, vascular congestion) was scored, and the correlation with the relative change in respiratory rate and survival was analyzed. This analysis showed the primary lesion to be radiation pneumonitis at a median survival time of approximately 100 days. Focal fibrosis was observed to occur soon thereafter, and no evidence was obtained for an independent second wave of fibrotic injury. Fibrosis seemed primarily the result of pathological organization in areas with heavy concentration of macrophages. It was observed that the mice were unusually sensitive, with a single dose X ray ED50/180 of 8.8 Gy. A similar value was found for unanesthetized mice. This might have been the result of performing these studies at an altitude of 2100 m. The fractionation effect also seemed more pronounced, with alpha/beta values of 0.6 Gy for X rays and 4 Gy for pions, which is significantly lower compared to reported values. At the pion dose-rate of 0.25 Gy.min-1, RBE values for single doses were 0.9 when compared to high dose-rate X rays, and 1.36 at equivalent dose rates. This clearly shows that significant repair occurs during the relatively low dose-rate pion irradiations. With smaller doses per fraction, the dose-rate effect became less dominant, and for 20 fractions of pions the RBE was 1.4 compared to fractionated high dose-rate X rays. These RBE's are similar to values reported for acute effects in skin.

Acute Disease↗
PubMed1987

Rapid assay for cell age response to radiation by electronic volume flow cell sorting.

A new technique is described for measuring cell survival as a function of cell cycle position using flow cytometric cell sorting on the basis of electronic volume signals. The sorting of cells into different cell age compartments is demonstrated for three different cell lines commonly used in radiobiological research. Using flow cytometric DNA content analysis and [3H]thymidine autoradiography of the sorted cell populations, we demonstrate that the resolution of the age compartment separation is as good as or better than that reported for other cell synchronizing techniques. The variation in cell survival as a function of position in the cell cycle after a single dose of radiation as measured by volume cell sorting is similar to that determined by other cell synchrony techniques. This new method has several advantages, including: no treatment of the cells is required, thus, this method is noncytotoxic; no cell cycle progression is needed to obtain different cell age compartments; the cell population can be held in complete growth medium at any desired temperature during sorting; and a complete radiation age-response assay can be plated in 2 h. The application of this method to problems in radiobiology and chemotherapy is discussed, along with some of the technical limitations.

Animals↗
PubMed1987

Radiobiology of ultrasoft X rays. I. Cultured hamster cells (V79).

Ultrasoft X rays (approximately less than keV) provide a useful probe for the study of the physical parameters associated with the induction of biological lesions because the spatial scale of their energy depositions is of nanometer dimensions, comparable to that of critical structures within the cell. We report on cell-killing experiments using cultured hamster cells (V79) exposed to carbon K (0.28 keV), aluminum K (1.5 keV), copper K (8.0 keV), and 250 kVp X rays, under oxic and hypoxic conditions, and as a function of cell-cycle phase. Our principal results are: RBE increases with decreasing X-ray energy; OER decreases with decreasing X-ray energy; and cell-cycle response is similar for all X-ray energies. Our RBE results confirm earlier observations using ultrasoft X rays on mammalian cells. The shapes of fitted curves through the data for each energy are statistically indistinguishable from one another, implying that the enhanced effectiveness is purely dose modifying. The results reported herein generally support the view that single-track effects of radiation are predominantly due to very local energy depositions on the nanometer scale, which are principally responsible for observed radiobiological effects.

Animals↗
PubMed1986

Mutational extinction induced by sequential X irradiation and actinomycin D treatments in Chinese hamster ovary cells.

The interactions of sequential X irradiation and actinomycin D (AMD) treatments for mutagenesis to 6-thioguanine resistance were investigated in CHO cells. Cells were exposed to single doses of X rays followed immediately by 1-h treatments with 0.1 or 1 microgram/ml AMD. X Rays alone induced mutagenesis which increased monotonically with dose to at least 8 Gy. AMD-treated control cultures showed slight to moderate cytotoxicity and little induced mutation. X Rays followed by AMD treatment produced bell-shaped mutagenesis dose-response curves with maximal mutation at approximately 5 or 4 Gy for 0.1 or 1.0 microgram/ml AMD, respectively. Induced mutation frequencies then fell to a negligible level at fractional survival levels below 0.10 for either combination treatment. Application of a stochastic Poisson distribution model to these data led to the prediction that two possible components govern induced mutation frequencies. First, X ray +AMD induced mutations may be depleted progressively with dose from the surviving populations by selective lethality, which we term mutational extinction. Second, X ray +AMD treatments were calculated to induce potentially much greater than additive mutagenesis. However, due to the overriding mutational extinction effect, most of these mutations are not recovered as viable colonies. These studies suggest that AMD binding to DNA immediately following irradiation may cause considerably enhanced mutagenic and often lethal DNA damage, and that mutational extinction may occur because these types of damage are statistically correlated in a sensitive subpopulation of exponentially growing CHO cells.

Animals↗
PubMed1985

Cell cycle-dependent Adriamycin uptake in Chinese hamster cells.

Adriamycin fluorescence was measured by flow cytometry after exposing synchronized Chinese hamster (line CHO) cells to a fixed dose of adriamycin (ADR). Three synchrony methods were used: mitotic selection, isoleucine-deficient culture and pretreatment with low doses of ADR. Approximately a 1.6- to 2-fold increase in ADR fluorescence intensity was observed for cells in G2 + M compared to cells in G1. An increase in ADR fluorescence was also noted for cell populations exhibiting a G2 block after pretreatment with low-dose ADR. No significant difference in fluorescence intensity was observed for G1 cell populations with two different volume distributions. Results suggest that the magnitude of ADR fluorescence is affected by the cell cycle distribution and that cellular susceptibility to drug-induced cytokinetic changes during exposure must also be taken into consideration when measuring ADR uptake.

Animals↗
PubMed1985

Effect of neon ions on synchronized Chinese hamster cells.

The variation in radiosensitivity across the cell cycle after exposure to neon ions and 60Co gamma-rays is reported for cultured hamster cells. The cells were first synchronized by mitotic selection, then resynchronized in the region of the G1/S boundary by treatment with 10(-3)M hydroxyurea. Although the use of hydroxyurea improves the synchrony, it does sensitize cells at the G1/S boundary to some degree. The cells were exposed at the plateau and the distal peak position of a neon ion beam modified by a 10 cm wide ridge filter. The results indicate that the variation (ratio of maximum to minimum survival after fixed doses of radiation that are approximately matched to produce similar cell killing) was approximately 80 to 100-fold for 60Co gamma-rays and neon ions at the plateau, and 25-fold for distal peak neon ions. While the r.b.e. of distal peak neon ions decreased rapidly with increasing dose for cells in late S-phase, the r.b.e. is independent of dose for cells at the G1/S boundary.

Animals↗
PubMed1984

Cell-cycle distributions and radiation responses of Chinese hamster cells cultured continuously under hypoxic conditions.

Cell-cycle distributions were measured by flow cytometry for Chinese hamster (CHO) cells cultured continuously under hypoxic conditions. DNA histograms showed an accumulation of cells in the early S phase followed by a traverse delay through the S phase, and a G2 block. During hypoxic culturing, cell viability decreased rapidly to less than 0.1% at 120 h. Radiation responses for cells cultured under these conditions showed an extreme radioresistance at 72 h. Results suggest that hypoxia induces a condition similar to cell synchrony which itself changes the radioresistance of hypoxic cells.

Animals↗
PubMed1984

Coulter volume cell sorting to improve the precision of radiation survival assays.

A new method for measuring cell survival at low doses of ionizing radiation has been developed through the use of flow cytometric cell sorting on the basis of Coulter volume signals. The cell sorter is capable of deflecting a precisely known number of cells directly into culture dishes, thus eliminating any errors associated with cell dilution and volume sampling. The use of Coulter volume signals as the sorting parameter is shown to be noncytotoxic for a variety of cell lines. Comparison of radiation survival curves measured above the 10% survival level by either the cell sorter or standard dilution assay demonstrates the increased precision of the cell sorter technique . Because of these advantages of cell sorting over conventional methods of plating cells, this technique has many applications in the field of radiation biology and other studies of cell survival.

Animals↗
PubMed1984

Flow cytometric determination of radiation-induced chromosome damage and its correlation with cell survival.

Chinese hamster M3-1 cells were irradiated with several doses of X rays or alpha particles from 238Pu. Propidium iodide-stained chromosome suspensions were prepared at different times after irradiation; cells were also assayed for survival. The DNA histograms of these chromosomes showed increased background counts with increased doses of radiation. This increase in background was cell-cycle dependent and was correlated with cell survival. The correlation between radiation-induced chromosome damage and cell survival was the same for X rays and alpha particles. Data are presented which indicate that flow cytometric analysis of chromosomes of irradiated cell populations can be a useful adjunct to classical cytogenic analysis of irradiation-induced chromosomal damage by virtue of its ability to express and measure chromosomal damage not seen by classical cytogenic methods.

Alpha Particles↗
PubMed1983

Correlations between cell-cycle perturbations and survival levels after exposure to adriamycin for two Chinese hamster cell lines.

The cell-cycle perturbation and cell inactivation after adriamycin (ADR) exposure were measured in two Chinese hamster cell lines differing in ADR sensitivity. Based on DNA distribution analysis, it was found that the rate of G1 fraction depletion following low-dose ADR treatment was related to the level of cell inactivation. The results indicate that gross cellular sensitivity to ADR can be predicted rapidly by this approach.

Animals↗
PubMed1983

Biological response across a ridge filter carbon ion Bragg peak.

The dose distribution of carbon ion beams was modified to cover 14 cm peak width using a ridge filter suitable for clinical application. The results of cell survival as a function of depth of penetration of carbon ions and the mouse skin (foot) response at the proximal-, mid-, and distal-peak positions using four daily fractions are reported. The objective of these studies is to verify whether the dose distribution in the peak region is properly compensated to produce uniform biological effect. The implications of the shape of the dose distribution in the peak region to radiotherapy application are discussed.

Animals↗