Thiol radioprotection<i>in vivo</i>: the critical role of tissue oxygen concentration

Denekamp, Juliana; Michael, B D; Rojas, Ana M.; Stewart, Fiona

doi:10.1259/0007-1285-54-648-1112-c

Cited by 51 publications

(11 citation statements)

References 18 publications

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“…Harris and Phillips (1971) first noted the critical role of oxygenation in WR-2721 protection, and recent work by Denekamp et al (1981Denekamp et al ( , 1982 quantified radioprotection of mouse skin as a function of oxygen concentration in the inspired gas in a manner qualitatively similar to the results reported here. Lung, which should be one of the betteroxygenated normal tissues, is only minimally protected by WR-2721(e.g.…”

Section: Discussionsupporting

confidence: 61%

Radioprotection by WR-2721 in vitro at low oxygen tensions: Implications for its mechanisms of action

Durand¹

1983

Br J Cancer

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Summary Radioprotection of spheroids of Chinese hamster V79 cells by WR-2721 was found to be a function of spheroid size, with the greatest dose-modifying effect by the protector observed for spheroids almost large enough to contain radioresistant "anoxic" cells. The nature of the response suggested that most of the protective effect was due to the presence of an increased hypoxic fraction in the drug-treated spheroids. Similarly, when single-cell suspensions were irradiated at various oxygen tensions, one component of radioprotection by WR-2721 was found to be highly dependent upon the available oxygen. Two mechanisms of radioprotection of V79 cells by WR-2721 were thus demonstrated: a modest, oxygen-independent effect, presumably due to hydrogen donation, and an oxygen-depleting effect, which is of maximal significance for cells or tissues which would otherwise be partially sensitized by low levels of oxygen.

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Section: Discussionsupporting

confidence: 61%

Radioprotection by WR-2721 in vitro at low oxygen tensions: Implications for its mechanisms of action

Durand¹

1983

Br J Cancer

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“…Thus the decrease in radiosensitization with fractionation was "mirrored" by an increase in radioprotection. Recent studies, using epidermal clones in vivo, have shown that the oxygen dependence of sulphydryl radioprotection is complex and depends on the precise oxygenation status, rather than simply on whether the cells are euoxic or hypoxic (Denekamp et al, 1981;. This agrees with in vitro studies with other sulphydryls, in bacteria and mammalian cells (Dewey, 1963;Cullen et al, 1980).…”

Section: Irradiationsupporting

confidence: 70%

Interaction of misonidazole and WR-2721—II. Modification of tumour radiosensitization

Rojas¹,

Stewart²,

Denekamp³

1983

Br J Cancer

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“…Thus, both in vitro and in vivo the maximum radioprotection was obtained in the region of the "K" value* for 2, i.e. in the region where small changes in the available 02 have the most marked effect on the radiosensitivity of the system (Denekamp et al, 1981. The early data of Dewey (1963) using very high concentrations of cysteine and highpressure 02 on Serratia marcescens accord with this conclusion.…”

Section: Competitive Interactionmentioning

confidence: 52%

“…The maximum radioprotection effect of dithioerythritol in vitro was obtained at 0.3%0 2, with less protection in anoxia or in air (Cullen et al, 1980). Similarly, using the epidermal colony assay in vivo, the maximum effect of WR 2721 was seen in air, being reduced in 100% 02 or in low 02 concentrations (Denekamp et al, 1981). Thus, both in vitro and in vivo the maximum radioprotection was obtained in the region of the "K" value* for 2, i.e.…”

Section: Competitive Interactionmentioning

confidence: 89%

“…Protection by sulphydryls is generally much greater in 02 than in hypoxic conditions (see Alper, 1979, for review). Recently, however, the dependence of radioprotection on the 02 concentration has been shown to be more complex (Lunec et al, 1981;Denekamp et al, 1981). The maximum radioprotection effect of dithioerythritol in vitro was obtained at 0.3%0 2, with less protection in anoxia or in air (Cullen et al, 1980).…”

Section: Competitive Interactionmentioning

confidence: 99%

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Interaction of radiosensitizers and WR-2721. I. Modification of skin radioprotection

Rojas¹,

Stewart²,

Denekamp³

1982

Br J Cancer

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Summary.-We have studied the radiomodifying action in mouse skin of WR-2721 and misonidazole (MISO) when used alone or in combination. The radioprotection with WR-2721 was drug-dose dependent and highly influenced by the 02 concentration at the time of irradiation. Significant sensitization was observed with MISO, especially in air-breathing mice. The combination of WR-2721 and MISO produced a radiation response intermediate between the resistant and sensitive responses to either drug alone. The precise degree of sensitivity was dependent on the relative doses of protector and sensitizer. We have also studied the interaction of both drugs in terms of drug-induced lethality, which showed a clear toxic interaction. The WR-2721 LD50 was reduced by a factor of 1-4 with only 200 mg/kg of MISO. We conclude that the combination of WR-2721 and MISO shows an interaction in terms of drug toxicity and radiation response, such that the radioprotection of skin is reduced or even abolished with low doses of MISO.

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Thiol radioprotectionin vivo: the critical role of tissue oxygen concentration

Cited by 51 publications

References 18 publications

Radioprotection by WR-2721 in vitro at low oxygen tensions: Implications for its mechanisms of action

Radioprotection by WR-2721 in vitro at low oxygen tensions: Implications for its mechanisms of action

Interaction of misonidazole and WR-2721—II. Modification of tumour radiosensitization

Interaction of radiosensitizers and WR-2721. I. Modification of skin radioprotection

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