Mammalian cell toxicity of nitro compounds: Dependence upon reduction potentiakl

Adams, G. E.; Clarke, Eric D.; Jacobs, Ruth; Stratford, Ian J.; Wallace, Raymond G.; Wardman, Peter; Watts, M.E.

doi:10.1016/s0006-291x(76)80207-0

Cited by 91 publications

(21 citation statements)

References 22 publications

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“…They are also selectively toxic to hypoxic cells in vitro (Adams et al, 1980;Stratford, personal communication). In the present work, the compounds when administered singly at 2-5 mmol/kg reduced MT tumourcell survival in situ by about 30% (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is known that hypoxic cytotoxicity of nitroimidazoles in vitro increases with electron affinity (Adams et al, 1980), it is not known what influence electron affinity has on the effectiveness of a nitroimidazole to potentiate the activity of chemotherapeutic agents. However, our data in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…ther, pretreatment in vitro of hypoxic cells with misonidazole renders the cells more sensitive to the cytotoxic action of some chemotherapeutic agents (Stratford et al, 1980). Several in vivo studies have shown that MISO apparently potentiates the anti-tumour activity of some chemotherapeutic drugs, particularly alkylating agents, in a variety of experimental tumours (Clement et al, 1980;Rose et al, 1980;Tannock, 1980;Siemann, 1981;Mulcahy et al, 1981;Law et al, 1981;Martin et al, 1981;Twentyman, 1981 (Sheldon & Hill, 1977), by subsequent monolayer cloning (McNally & Sheldon, 1977) and by subsequent soft-agar cloning Clonogenic assay.-Tumour response was assayed by a modification of the soft-agar cloning technique described by Stephens et al (1980).…”

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confidence: 99%

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Potentiation of melphalan activity against a murine tumour by nitroimidazole compounds

Sheldon¹,

Batten²,

Adams³

1982

Br J Cancer

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Summary.-The activity against murine anaplastic MT tumours of the chemotherapeutic agent melphalan, either alone or in combination with one of 6 nitroimidazole compounds, was assayed using an in vivo-in vitro tumour excision assay. The melphalan alone proved cytotoxic to the tumour, whereas relatively little cytotoxicity was produced by any of the nitroimidazoles alone. When the nitroimidazole were given in combination with melphalan, dose-modifying potentiation of its cytotoxicity was observed. Maximum potentiation occurred when the nitroimidazoles were given 0-30 min before the melphalan, although some potentiation was still evident when they were given up to 2 h before or after. There was no threshold in nitroimidazole dose required to produce this potentiation, the degree of potentiation increrasing with dose, albeit at a diminishing rate, to give maximum dose-modification factors of about 3.The 6 nitroimidazole compounds in order of increasing effectiveness as potentiators of melphalan activity were: METRO, Ro 05-9963, MISO, RSU 1047, Ro 03 -8800 and Ro 03 -8799. This order corresponds to the increasing electron affinity of these compounds. The most effective compound here, Ro 03-8799, was about twice as effective as the most widely used nitroimidazole in such studies, MISO.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Potentiation of melphalan activity against a murine tumour by nitroimidazole compounds

Sheldon¹,

Batten²,

Adams³

1982

Br J Cancer

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“…These drugs are also known to be mutagenic and toxic to mammalian cells (15). The enzymatic formation of the nitro anion free radical is thought to play a key role in both the biological activity and toxicity of nitroaromatic compounds (3,4).…”

Section: R-no1 -H--r-nhoh H R-nh2mentioning

confidence: 99%

“…The enzymatic formation of the nitro anion free radical is thought to play a key role in both the biological activity and toxicity of nitroaromatic compounds (3,4). Since the ease of formation of the nitro anion radical is related to the oneelectron reduction potential (EW) ofthe parent compound attempts have been made to correlate biological activity with this parameter (15)(16)(17)(18)(19)(20).…”

Section: R-no1 -H--r-nhoh H R-nh2mentioning

confidence: 99%

Structure-activity relationships in the free-radical metabolism of xenobiotics.

Chignell¹

1985

Environ Health Perspect

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Many xenobiotics, including naturally occurring compounds, drugs, and environmental agents, are metabolized both in vivo and in vitro to free-radical intermediates. The one-electron reduction of nitroaromatic compounds, quinones, and a wide variety of other chemicals is catalyzed enzymatically by a number of reductases and dehydrogenases. Structure-activity studies have shown that the cytotoxicities of nitroaromatic compounds and quinones are related to their one-electron reduction potentials (EW). Other factors such as oil:water partition coefficients may also be important. Xenobiotics may also be oxidized to free radicals by peroxidases and oxidases. Hammett's rules apply to the one-electron oxidation of simple meta-or para-substituted phenols and amines by horseradish peroxidase, compound I.

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Polarographic and electrochemical studies of some aromatic and heterocyclic nitro compounds: Part V. Polarographic reduction of cyano‐and carboxamido‐nitropyrazoles

Dumanović¹,

Jovanović²,

Marjanović³

et al. 1993

Electroanalysis

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Reduction of the nitro group in l-alkyl-4-cyano-5-nitropyrazoles follows a pattern similar to that of 1-alkyl-5-nitropyrazoles, involving the sequence H+, e, H+, e, 2e, 2H+. On the other hand, the sequence of proton and electron transfers in the reduction of the nitro group in l-alkyl-3-nitro-4-cyanopyrazoles differs from that in 1-alkyl-3-nitropyrazoles. Similarly, the reduction of 4-cyano-3( 5)-nitropyrazole differs from that of 3(5)-nitropyrazole, even when both of these reductions are affected by the dissociation of the NH group with pK, = 6.26 and 9.81, respectively. Similarly, the behavior of I-alkyl-4-carboxamido-5-nitropyrazoles resembles that of l-alkyl-5-nitropyrazoles, but that of l-alkyl-3-nitro-4-carboxamidopyrazoles is different from that of 1-alkyl-3-nitropyrazoles. In l-alkyl-4-carboxamido-5-hydroxylaminopyrazoles, the carboxamido group is reduced in a two-and four-electron process, but the low absolute value of the limiting current of wave i2 indicates the presence of competitive side reactions.

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Mammalian cell toxicity of nitro compounds: Dependence upon reduction potentiakl

Cited by 91 publications

References 22 publications

Potentiation of melphalan activity against a murine tumour by nitroimidazole compounds

Potentiation of melphalan activity against a murine tumour by nitroimidazole compounds

Structure-activity relationships in the free-radical metabolism of xenobiotics.

Polarographic and electrochemical studies of some aromatic and heterocyclic nitro compounds: Part V. Polarographic reduction of cyano‐and carboxamido‐nitropyrazoles

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