A water-soluble extract of the root of Panax ginseng, a plant native to northeastern China, was fractionated into three components: carbohydrate, protein, and saponin fractions. The fractions obtained were tested for their ability to protect against the lethal effects of 60Co gamma irradiation in C3H mice. The results were compared to the protective ability of the water-soluble fraction of whole ginseng. An experiment designed to test the optimum time of injection of whole ginseng showed that administration 24 h prior to irradiation was optimal. Ginseng extract or one of its three fractions was dose adjusted and injected intraperitoneally into mice that 24 h later were irradiated, whole body, with doses ranging from 7 to 11 Gy. The LD50 in 30 days was calculated using Probit analysis. The results indicated that the water soluble extract of whole ginseng gave the best protection against gamma radiation. The isolated protein and carbohydrate fractions gave less protection, while the saponin fraction did not protect.
Summary Radiation induced DNA double strand breaks are believed to be important lesions involved in processes related to cell killing, induction of chromosome aberrations and carcinogenesis. This paper reports the effects of the radioprotector 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation-induced DNA damage and repair in V79 cells using the neutral elution method performed at pH 7.2 or pH 9.6. WR-1065 (4mM) was added to the culture medium either 30 minutes prior to and during irradiation with Cobalt-60 gamma rays (for dose response experiments) or during the repair times tested (for DNA rejoining experiments). The results indicate that WR-1065 is an effective protector against the formation of radiationinduced double-strand breaks in DNA as measured using a neutral elution technique at either pH. The protector reduced the strand scission factors by 1.44 and 1.77 in experiments run at pH 9.6 and pH 7.2, respectively.The kinetics of DNA double-strand rejoining were dependent upon the pH at which the neutral elution procedure was performed. Unlike the results obtained with alkaline elution, rejoining of DNA breaks was unaffected by the presence of WR-1065 at either pH.
The ability of the compound S-2-(aminopropylamino)ethylphosphorothioic acid, designated WR-2721, to protect against neutron-induced carcinogenesis was investigated. Both sexes of the B6CF1 mouse were injected i.p. with 400 mg/kg of WR-2721 30 min prior to being irradiated by 10 cGy of neutrons. Neoplastic mortality in the groups receiving thiol was either reduced or delayed relative to irradiated mice not given protector. However, the time at which the protective effect of WR-2721 was expressed depended on the sex of the animal. Thiol-related shifts in the time of neoplastic death in females occurred only in the first half of the lifespan. Once a female survived to the mean age at death, no difference in the pattern of mortality could be detected between control and WR-2721-treated mice exposed to neutrons. Irrespective of thiol treatment, the timing of tumour-related death was nearly identical during the first half of life for males exposed to neutrons. In the last half of the lifespan, survival of thiol-protected males was enhanced relative to saline-injected males and even exceeded that observed in the control population.
Summary The effect(s) of the radioprotector 2-[(aminopropyl)amino] ethanethiol (WR1065) on fissionneutron-induced DNA damage and repair in V79 Chinese hamster cells was determined by using a neutral filter elution procedure (pH7.2). When required, WR1065, at a final working concentration of 4mM, was added to the culture medium, either 30min before and during irradiation with fission spectrum neutrons (beam energy of 0.85MeV) from the JANUS research reactor, or for selected intervals of time following exposure. The frequency of neutron-induced DNA strand breaks as measured by neutral elution as a function of dose equalled that observed for 60Coy-ray-induced damage (relative biological effectiveness of one). In contrast to the protective effect exhibited by WR1065 in reducing 60Co-induced DNA damage, WR1065 was ineffective in reducing or protecting against induction of DNA strand breaks by JANUS neutrons. The kinetics of DNA double-strand rejoining were measured following neutron irradiation. In the absence of WR1065, considerable DNA degradation by cellular enzymes was observed. This process was inhibited when WR1065 was present. These results indicate that, under the conditions used, the quality (i.e. nature), rather than quantity, of DNA lesions (measured by neutral elution) formed by neutrons was significantly different from that formed by y-rays.WR 1065 is the corresponding free thiol of the wellcharacterised radioprotector S-2-(3-aminopropylamino) ethyl phosphorothioic acid designated WR2721 (Purdie, 1979). The current clinical interest in these and similar compounds stems from early reports that these agents can preferentially protect normal as compared to neoplastic tissues against both acute and late-arising radiation-and/or chemotherapyinduced injuries (Yuhas, 1979;Phillips, 1980;Glover et al., 1984;Kligerman et al., 1984). Thiol compounds such as WR2721 and cysteamine have also been reported to be effective in protecting against oncogenesis in a number of experimental rodent systems (Marquardt et al., 1974;Apffel et al., 1975;Takeuchi & Murakami, 1978;Milas et al., 1984;Grdina et al., 1985b).WR1065 and cysteamine can both protect against radiation induced mutagenesis at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus in mammalian cells (Grdina et al., 1985a;Corn et al., 1987). WR1065 has also been found to be effective in protecting against the induction of HGPRT mutants by cisplatin , bleomycin and nitrogen mustard (Nagy & Grdina, 1986) and the transformation of 10T1/2 cells by ionizing radiation (Hill et al., 1986).Linked to the expression of each of these deleterious endpoints are, presumably, factors involving DNA damage and repair. It is well known that selected aminothiol compounds can protect against the induction of single-and double-strand breaks in the DNA of irradiated cells (LaSalle & Billen, 1964;Sawada & Okada, 1970;Billen, 1983;Grdina & Nagy, 1986;Sigdestad et al., 1987;Murray et al., 1988 Accordingly, the US Government retains a non-exclusive, royaltyfree licence to pu...
Summary The radioprotector 2-[(aminopropyl)amino] ethanethiol (WR1065) was investigated with respect to its ability to affect radiation-induced DNA damage and repair in V79 cells. Studies were performed to evaluate the protector under conditions in which it is known to be effective in reducing the cytotoxic and mutagenic effects of y-irradiation. At a concentration of 4mM, WR1065 protected against the formation of single strand breaks (SSB), as determined by the method of alkaline elution, when it was present during irradiation. The protector appeared, however, to inhibit the subsequent postirradiation repair or rejoining of SSB. While repair was complete within 24h, the protector reduced the rate of repair by a factor of 3. This inhibitory effect on the rate of repair did not correlate with either measured differences in cell survival or mutagenesis. The radioprotector was also investigated with respect to its ability to affect cell cycle progression. WR1065 present in the growth medium inhibited the progression of cells through S-phase, and cell-doubling time following a 3 h exposure to the protector was increased from 11 to 18 h. These data are consistent with the well characterized property of thiols to inhibit DNA polymerase activity. It was concluded that, while the presence of WR1065 during irradiation reduced SSB-DNA damage, its effect on the subsequent rejoining of these breaks could not be correlated with its observed effect on protecting against radiation-induced mutagenesis. It may be that the inhibition of cell-cycle progression by the protector allowed more time to enhance the fidelity of repair as measured by the protector's ability to protect against radiationinduced mutagenesis.
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