[en] The authors investigated the protective effects of WR2721 on the induction by radiation of altered hepatocyte foci in 150-day-old Sprague Dawley rats. One hundred micrograms of WR2721 per gram of body weight were administered to selected groups of neonatal animals 30 min prior to the administration of single doses of γ irradiation (150 or 300 rad). Focus pheotypes, gamma-glutamyltranspeptidase (GGT) and/or the iron exclusion histochemical markers, were quantitated through the use of serial frozen sectioning techniques and computer-assisted image analysis. Radiation was effective in inducing foci formation. Induction was much more effective in female as compared to male rats. WR2721 reduced the frequencies of radiation-induced foci at both radiation doses, with the greatest effect apparent in female rats. The protective effect of WR2721 in this system suggests that this compound and related aminothiols may be useful probes for examining mechanisms of mutagenesis and carcinogenesis induced by radiation or chemicals

[en] WR1065 protects against radiation-induced cell killing and mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus in V79 Chinese hamster lung fibroblast cells. At a concentration of 4 mM, WR1065 effectively protected against cell death only if present during irradiation, e.g., a dose modification factor (DMF) of 1.9. No protective effect was observed if WR1065 was added within 5 min after irradiation or 3 h later, e.g., DMFs of 1.0 and 1.1, respectively. In contrast, WR1065 effectively reduced radiation-induced mutations regardless of when it was administered. Following a dose of 1000 rad of /sup 60/Co γ rays, the mutation frequencies observed per 10/sup 6/ survivors were 77+-8, 27+-6, 42+-7, and 42+-7 for radiation only, and WR1065 present during, immediately after, or 3 h after irradiation. These data suggest that although a segment of radiation induced damage leading to reproductive death cannot be modulated through the postirradiation action of WR1065, processes leading to the fixation of gross genetic damage and mutation induction in surviving cells can be effectively altered and interfered with leading to a marked reduction in mutation frequency

[en] The effect of 2[(aminopropyl)amino]ethanethiol (WR1065) has been studied on the induction of neoplastic transformation using 10T1/2 cells and on mutation of the hypoxanthine guanine phosphoribosyl transferase (HGPRT) locus using Chinese hamster V79 cells. The first observations that treatment of 10T1/2 cells with 1 mM WR1065 for a total of 35 min during irradiation with ⁶⁰C γ-rays significantly reduces the incidence of neoplastic transformation while having no effect on cell viability are reported. In a similar experiment with V79 cells in which 4mM WR1065 was used, a significant reduction in mutation frequency at the HGPRT locus and significant protection against cell killing was found. These results suggest that WR1965 acts to modulate both acute damage and sub-lethal processes that lead to mutation and neoplastic transformation. Beyond the purely mechanistic approach of these studies, the potential application of these agents to minimizing the long-term neoplastic effects of radiation or chemotherapeutic agents currently in use for treating potentially curable cancer patients should be further investigated. (author)

[en] Brief item

[en] Purpose: To assess the effect of pre-treatment Magnetic Resonance Imaging (MRI) on cell survival following orthovoltage radiation therapy. Methods: This in vitro study examined the survival of FSa cells (extracted from methylcholanthrene-induced fibrosarcoma in the flank of a C3H female mouse) and SA-NH cells (derived from a spontaneously arising murine sarcoma tumor) having undergone an MRI scan prior to radiation exposure. Cell cultures were kept at 37 C, in a humidified environment with 5% CO2, and were grown to confluence prior to the start of the experiment. Each cell culture underwent two, 25 minute MRIs spaced 24 hours apart using a standard brain imaging protocol. The cultures were exposed to a 2 Gy dose of radiation beginning 15 minutes after the end of each MRI scan. Irradiations were performed by a Philips RT250 X-ray generator at 250 kVp and 15 mA. All MR imaging was performed on a 1.5 T Philips Achieva scanner using a head and neck vasculature coil. Results: Cells given an MRI scan prior to radiation exhibited an increase in mean surviving fraction of 10.8% and 9.6% in FSa and SA-NH cells, respectively. The difference was found to be statistically significant in both cell types by a student two-tailed t test with P = 0.011 and P < 0.001 for FSa and SA-NH, respectively. Conclusion: MRI may cause an increase in radio-resistance in FSa and SA-NH cells. If this biological effect is found to be consistent across other cell types and voltage ranges, these results could help inform treatment planning by improving our understanding of the joint effects of MRI and ionizing radiation. This work was supported in part under NIH grant numbers T32 EB002103, NCI R01-CA 132998, DOE Low Dose Program/Project Grant DE-413 SC0001271. DJ Grdina is a paid consultant to Pinnacle Biologics. DJ Grdina and JS Murley are minority equity partners in Pinnacle Oncology LLC.

[en] WR-2721 (S-2-[3-aminopropylamino] ethylphosphorothioic acid) significantly reduced the number of radiation-induced tumors in C/sub 3/H mice. The authors therefore tested WR-2721 and a related compound, WR-1065 (N-[2-mercaptoethyl]-1,3 diaminopropane), for toxicity, mutagenicity, and transformation in several systems. In V79 Chinese hamster cells, 100% survival occurred after 3-hr exposures to either 1 mM or 10 mM levels of WR-2721; similar exposures to WR-1065 yielded about 60% (1 mM) and 80% (10 mM) survival levels. Using resistance to 6-thioguanine in the V79 cells as the index of mutagenicity, they found the mutation frequency (uncorrected for background) to range from 11 x 10/sup -6/ to 44 x 10/sup -6//surviving cell. In vivo transformation studies in newborn Sprague Dawley rats revealed an unexpected toxicity; all animals given doses of 200 and 400 mg/kg of WR-2721 died within 24 hr. No host toxicity was observed at doses of 50 or 100 mg/kg. The role of WR-2721, administered alone or in combination with radiation and/or diethylnitrosamine (DEN), in liver foci and tumor formation is discussed

[en] alpha-Emitting radionuclides may be an effective alternative treatment against ovarian carcinoma because they have short half-lives and are densely ionizing, with high linear energy transfer to a depth of several cell diameters without requiring cellular oxygenation. One radionuclide that has been generated and tested in our laboratory in vitro and in vivo is lead 212 (²¹²Pb). Intraperitoneal instillation of ²¹²Pb prolonged survival and totally eradicated tumor in 24% of mice inoculated with the extremely virulent Ehrlich ascites-producing tumor. In vitro ²¹²Pb was two to four times more effective in killing human ovarian cancer cells than x-rays. Irradiation with ²¹²Pb increased the radiosensitivity and chromosomal aberrations of cells. In dogs, intraperitoneal instillation of 2.6 mCi of ferrous hydroxide tagged with ²¹²Pb caused no significant toxicity. It appears that alpha-emitting radionucides such as ²¹²Pb have the potential to be a new and potent treatment of ovarian carcinoma and could be effective in cases that are resistant to conventional chemotherapy or x-ray therapy

[en] Damage to lens epithelial cells is a probable initiation process in cataract formation mediated by UV radiation. In these experiments, we investigated the effects of exposure to 254 nm radiation on cell cycle progression in the rabbit lens epithelial cell line N/N1003A. The RNA was harvested at various times following exposure to UV (254 nm) radiation and analyzed by dot-blot and northern blot hybridizations. These results revealed that during the first 6 h following exposure of the cells to UV, there was, associated with decreasing dose, a decrease in accumulation of transcripts specific for histones H3 and H4 and an increase in the mRNA encoding protein kinase C and β- and γ-actin. Using flow cytometry, we detected an accumulation of cells in G1/S phase of the cell cycle 1 h following exposure to 254 nm radiation. The observed changes in gene expression, especially the decreased accumulation of histone transcripts reported here, may play a role in UV-induced inhibition of cell cycle progression. (Author)

[en] Calcium is required as a cofactor by primer recognition proteins involved in DNA synthesis and by protein kinase C (PKC), which is activated by ionizing radiation. Because these processes may be involved in radiation-mediated regulation of the progression of cells through the phases of the cell cycle, we studied the effects of the intracellular Ca²⁺ chelator, acetoxymethyl-1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (AM-BAPTA), on PKC activation, expression of c-jun and Gadd45 and distribution of cells in the phases of the cell cycle after irradiation. AM-BAPTA prevented ionizing-radiation-induced activation of PKC and expression of c-jun in cells of humor tumor cell lines. Conversely, calcium chelation had no effect on X-ray-induced expression of the Gadd45 gene. To determine whether changes in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) occurred during irradiation, we measured [Ca²⁺]_i in single cells using fura-2-based microfluorimetry. There was no increase in [Ca²⁺]_i during or after irradiation of cells of the human tumor cell lines RIT-3, SQ-20B or HL-60 or normal human fibroblast strain IMR-90. The percentage of human tumor cells crossing the G₁/S-phase border was reduced by pretreatment with AM-BAPTA. These data indicate that calcium is required for ionizing radiation-induced cell cycle regulation and PKC activation, but that increases in [Ca²⁺]_i do not occur in cells of the cell lines irradiated in this study. 46 refs., 7 figs., 1 tab

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