The radioprotector WR1065 reduces radiation-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in V79 cells

Abstract

N-(2-mercaptoethyl)-1,3-diaminopropane (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 was found to be effective in protecting against radiation-induced cell lethality only if present during irradiation, e.g., a dose modification factor (DMF) of 1.9. No protective effect was observed if the protector was added within 5 min after irradiation or 3 h later, e.g., DMFs of 1.0 and 1.1, respectively. The effect of WR1065 on radiation-induced mutation, expressed as resistance to the cytotoxic purine analogue 6-thioguanine (HGPRT), was also investigated. In contrast to the treatment-schedule dependence for protection by WR1065 against cell killing, this agent was effective in reducing radiation-induced mutations regardless of when it was administered. Following a dose of 10 Gy of 60Co gamma-rays, the mutation frequencies observed per 10(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.

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

“…Two concentrations of WR1065 were chosen for investigation. WR1065 when present during irradiation at a concentration of 4 mM can significantly protect cells from radiation toxicity [12,13,27]. This effect is best described as immediate radioprotection and is routinely demonstrated by administering WR1065 30 min prior to irradiation.…”

“…This effect is best described as immediate radioprotection and is routinely demonstrated by administering WR1065 30 min prior to irradiation. The radioprotective effect, however, diminishes rapidly as the concentration of WR1065 is reduced [12,13,27]. At a concentration of 40 μM, WR1065 is ineffective for protection against cell killing but is sufficient for preventing radiation-induced mutagenesis through a distinctly separate mechanism of action [13].…”

“…Therefore, to be effective agents such as amifostine must be administered shortly before radiation exposure. Administration following irradiation is ineffective in affording protection against free radical damage [12,13].…”

The effect of 2-[(aminopropyl)amino] ethanethiol (WR-1065) on radiation induced DNA double strand damage and repair in V79 cells

“…This suggestion was confirmed by Milas et al (1984), who reported the anticarcinogenic effect of WR-2721 in irradiated mice. In addition, protectors have been shown to be antimutagenic (Grdina et al, 1985a; and antineoplastic (Hill et al, 1986) and to reduce the formation of radiation-induced preneoplastic foci in rats (Grdina et al, 1985b).…”

“…Because some workers have suggested (Tilby et al, 1984;Evans et al, 1986) that DNA elution at pH9.6 modifies the quality of breaks, we assayed DSB formation both at pH 9.6 and pH7.2. (Grdina et al, 1985a;Nagy et al, 1986a (Meyn & Jenkins, 1983). In the DNA repair studies, a single cell suspension was irradiated, on ice, with a dose of 25krad (250Gy).…”