Cytotoxicity and DNA damage to mammalian cells by nitrofurans

Olive, Peggy L.; McCalla, D. R.

doi:10.1016/0009-2797(77)90131-4

Cited by 75 publications

(27 citation statements)

References 12 publications

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“…Previous results (Olive, 1976) indicated that nitrofurazone inhibits ATP synthesis in I, cells incuibated for 2 h at concentrations over 100 KtM. This inhibition occurred under both aerobic and anaerobic incubation, similar to the effects on inhibition of DNA initiation, suggesting that decreases in the level of ATP inhibit DNA synthesis.…”

Section: Resultssupporting

confidence: 60%

Inhibition of DNA synthesis by nitroheterocycles. II. Mechanisms of cytotoxicity

Olive¹

1979

Br J Cancer

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Section: Resultssupporting

confidence: 60%

Inhibition of DNA synthesis by nitroheterocycles. II. Mechanisms of cytotoxicity

Olive¹

1979

Br J Cancer

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“…Similar reductive processes have been proposed to account for their toxicity towards mammalian cells (Olive & McCalla, 1975). In bacteria, DNA has been implicated as the target mainly responsible for cytotoxic (McCalla et al, 1971(McCalla et al, , 1978 and mutagenic effects (Cohen & Bryan, 1973) of these compounds.…”

Section: Discussionmentioning

confidence: 81%

“…In bacteria, DNA has been implicated as the target mainly responsible for cytotoxic (McCalla et al, 1971(McCalla et al, , 1978 and mutagenic effects (Cohen & Bryan, 1973) of these compounds. In mammalian cells exposure to nitrofurans produces single-strand breaks in DNA (Olive & McCalla, 1975), though this has not been shown to be the toxic event. Varghese & Whitmore (1980) have suggested nitroreduction and the binding of nitroreduced products to macromolecules as a probable mechanism for the mutagenic and cytotoxic properties of MISO.…”

Section: Discussionmentioning

confidence: 99%

“…Nitro-aromatic compounds such as MISO can be reduced by some enzymes acting as nitroreductases, which could lead to the production of toxic radical anions, superoxide radicals and H202 (Biaglow et al, 1977;Mason & Holtzman, 1975). For example, such enzyme activity has been proposed to account for the toxicity of nitrofuran radiosensitizers in mammalian cells in vitro (Olive & McCalla, 1975).…”

mentioning

confidence: 99%

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Flurbiprofen, a non-steroid anti-inflammatory agent, protects cells against hypoxic cell radiosensitizers in vitro

Millar¹,

Jinks²,

Powles³

1981

Br J Cancer

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Summary.-Overnight exposure of Chinese hamster cells (V79-753B) to 5 x 10-5M flurbiprofen (2-(2-fluoro-4-biphenyl)propionic acid) in vitro reduced the cytotoxic effects of misonidazole, 1-methyl -4-nitro -5 -phenoxysulphonylimidazole (NSC 38087) and nitrofurantoin, both in air and in hypoxia at 37°C. Flurbiprofen did not alter the cells' uptake of 14C-misonidazole, nor did it affect the radiosensitivity of aerobic or anaerobic cells, or the degree of hypoxic-cell radiosensitization produced by the sensitizers. When flurbiprofen-treated cells were exposed to melphalan there was no protection against cytotoxicity. These data suggest that flurbiprofen may inhibit the catabolism of radiosensitizers to toxic products and indicate the need to examine whether it will protect against misonidazole-induced toxicity in vivo.

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“…Clearly, their presence in human tumours may limit the effectiveness of cancer therapy. Development of hypoxic cell radiosensitizers thus has a clear rationale; the observations that many of these sensitizers were preferentially toxic to hypoxic cells (Olive & McCalla 1975; Hall & Roizin-Towle 1975;Moore et al, 1976) suggested that they may be complementary to many conventional cancer chemotherapeutic agents, and could thus be used effectively in combination treatments. Indeed, in a number of instances an interaction between the sensitizer and the chemotherapeutic agent was observed (Kelly et al, 1979;Clement et al, 1980;Rose et al, 1980, and reviewed by Siemann, 1984).…”

mentioning

confidence: 99%

Chemosensitization by misonidazole in CCNU-treated spheroids and tumours

Durand

Dj²

1987

Br J Cancer

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Summary Misonidazole has been demonstrated to enhance the cytotoxicity of several common antineoplastic drugs in vitro and in vivo, and its mechanism of action as a chemosensitizer, though still unknown, is thought to be dependent upon hypoxia. We have used fluorescence-activated cell sorting to evaluate chemopotentiation by misonidazole as a function of cell position in V79 spheroids and KHT tumours. CCNU toxicity was enhanced in all cell subpopulations of both tumours and spheroids, with greater consistency than might be predicted on the basis of the known variations in oxygen tension. Further, both misonidazole and CCNU as single agents were preferentially toxic in the less well oxygenated regions of each system, arguing that differential toxicity canno t be implicated in the chemopotentiation observed. In fact, increased treatment toxicity did not necessarily lead to increased chemopotentiation, nor was potentiation directly related to the metabolism/binding of the misonidazole. Chemopotentiation in multicell systems thus appears to be a complex, multi-factorial process.Hypoxic cells develop spontaneously during the growth of many solid tumours, and are known to be resistant to ionizing radiation and implicated in resistance to several antineoplastic drugs. Clearly, their presence in human tumours may limit the effectiveness of cancer therapy. Development of hypoxic cell radiosensitizers thus has a clear rationale; the observations that many of these sensitizers were preferentially toxic to hypoxic cells (Olive & McCalla 1975; Hall & Roizin-Towle 1975;Moore et al., 1976) suggested that they may be complementary to many conventional cancer chemotherapeutic agents, and could thus be used effectively in combination treatments. Indeed, in a number of instances an interaction between the sensitizer and the chemotherapeutic agent was observed (Kelly et al., 1979;Clement et al., 1980;Rose et al., 1980, and reviewed by Siemann, 1984).Many factors have been implicated in the phenomenon of chemosensitization (see Brown 1982, and Siemann 1984 for reviews), including differential toxicity (Kelly et al., 1979), direct interactions between the sensitizer (or its toxic metabolites, which are generally produced under hypoxic conditions) and the chemotherapeutic agent itself (Taylor et al., 1982), alterations of drug pharmacology or delivery (Urtasun et al., 1982;Workman et al., 1983;Lee & Workman 1986), inhibition of repair processes by chemosensitizer treatment (Taylor et al., 1982;Mulcahy 1986), and alterations of cellular drug sensitivity, by, for example, the sensitizer selecting for surviving cells more vulnerable to the chemotherapeutic agent due to cell cycle status or other factors . Perhaps the most consistent observation, however, has been the apparent requirement of hypoxia both in vitro (Brown, 1982;Mulcahy, 1984), and in vivo Wheeler et al., 1984).In this report, we present data evaluating the cytotoxic effects of misonidazole, MISO, and N-(2-chloro-ethyl)-N'-cyclohexyl-N-nitrosourea, CCNU, singly and in combi...

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Cytotoxicity and DNA damage to mammalian cells by nitrofurans

Cited by 75 publications

References 12 publications

Inhibition of DNA synthesis by nitroheterocycles. II. Mechanisms of cytotoxicity

Inhibition of DNA synthesis by nitroheterocycles. II. Mechanisms of cytotoxicity

Flurbiprofen, a non-steroid anti-inflammatory agent, protects cells against hypoxic cell radiosensitizers in vitro

Chemosensitization by misonidazole in CCNU-treated spheroids and tumours

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