I want to assess the toxicity of nitro compounds toward hypoxic mammalian cancer cells in vitro, and check out whether the nitro based compounds gets reduced to respective amines utilising the hypoxic conditions of the cancer microenvironment, i.e., in the absence of 2% O2 (Maintained via incubator).
Any literature or suggestions in this regards will be appreciable.
http://www.ncbi.nlm.nih.gov/pubmed/6928241
1-Br J Cancer. 1984 Feb; 49(2): 215–223. (see attached paper).
PMCID: PMC1976693
Selective toxicity of nitracrine to hypoxic mammalian cells.
W. R. Wilson, W. A. Denny, S. J. Twigden, B. C. Baguley, and J. C. Probert
Copyright and License information ►
Abstract
Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.
2-Environ Health Perspect. 1985 Dec; 64: 199–208. (see attached file).
PMCID: PMC1568619
Research Article
Mechanism of toxicity of nitro compounds used in the chemotherapy of trichomoniasis.
S N Moreno and R Docampo
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
The mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin-mediated reduction of their nitro group, with generation of a reactive metabolite or metabolites which interact with DNA leading to a subsequent inhibition of nucleic acid and protein synthesis. Redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs, thereby inhibiting their uptake. On the other hand, redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady-state concentrations of oxygen-derived metabolites that might be of toxicological significance. It seems likely that reduced metabolites of nitroimidazoles (perhaps through covalent binding to tissue macromolecules and/or thiols depletion) are also involved in the nitroimidazoles' toxic effects to animal tissues and in their mutagenic and carcinogenic action.
3-Br J Cancer. 1981 Jul; 44(1): 109–116. (see attached file).
PMCID: PMC2010648
Cytotoxic properties of a 4-nitroimidazole (NSC 38087): a radiosensitizer of hypoxic cells in vitro.
I. J. Stratford, C. Williamson, and C. Hardy
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
5-Phenoxysulphonyl-1-methyl-4-nitroimidazole (NSC 38087) can act as a sensitizer of hypoxic mammalian cells to radiation in vitro. The degree of sensitization achieved is greater than would be predicted from the drug's electron affinity. Cytotoxicity studies have shown that 5 microM NSC 38087 can reduce the surviving fraction of log-phase V79 cells in air at 37 degrees C to 10(-2) after 2 h exposure. This toxicity is considerably increased by small rises in temperature. In contrast to other nitro-heterocyclic radiosensitizers, NSC 38087 and related 5-substituted 4-nitroimidazoles show greater toxicity towards aerobic than to hypoxic cells. Log-phase cells show the highest sensitivity to the toxic action of NSC 38087, with plateau-phase cells, cells with a history of chronic hypoxia, and thermotolerant cells showing greater resistance. These toxicity data are compared to those for the 2-nitroimidazole hypoxic-cell sensitizer misonidazole.
4-Br J Cancer. 1981 Mar; 43(3): 350–354. (see attached file).
PMCID: PMC2010608
Cytotoxicity of metronidazole (Flagyl) and misonidazole (Ro-07-0582): enhancement by lactate.
J. S. Mahood and R. L. Willson
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
The cytotoxic activity of metronidazole (Flagyl) and misonidazole (MISO) to hypoxic Chinese hamster ovary (CHO) cells suspended in standard medium in sealed vials and in gassed spinner flasks has been investigated. Flagyl (5 mM) was only cytotoxic at high initial cell densities. However, when lactate (20 mM) was included in the medium the cytotoxicity of Flagyl at low cell densities was considerable, and similar to that of misonidazole under the same conditions. The relevance of this "lactate effect" to in vivo systems, and the possible mechanisms involved, are discussed.
5-Mechanism of Toxicity of Nitro Compounds (see attached file).
Used in the Chemotherapy of
Trichomoniasis
by Silvia N. J. Moreno* and Roberto Docampo*
The mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin-mediated reduction of their nitro group, with generation of a reactive metabolite or metabolites which interact with DNA leading to a subsequent inhibition of nucleic acid and protein synthesis. Redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs, thereby inhibiting their uptake. On the other hand, redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady-state concentrations of oxygen-derived metabolites that might be of toxicological significance. It seems likely that reduced metabolites of nitroimidazoles (perhaps through covalent binding to tissue macromolecules and/or thiols depletion) are also involved in the nitroimidazoles' toxic effects to animal tissues and in their mutagenic and carcinogenic action
Hoping this will be helpful,
Rafik
Dear Gaurav,
The following papers might be helpful.
1-Br J Cancer. 1984 Feb; 49(2): 215–223. (see attached paper).
PMCID: PMC1976693
Selective toxicity of nitracrine to hypoxic mammalian cells.
W. R. Wilson, W. A. Denny, S. J. Twigden, B. C. Baguley, and J. C. Probert
Copyright and License information ►
Abstract
Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.
2-Environ Health Perspect. 1985 Dec; 64: 199–208. (see attached file).
PMCID: PMC1568619
Research Article
Mechanism of toxicity of nitro compounds used in the chemotherapy of trichomoniasis.
S N Moreno and R Docampo
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
The mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin-mediated reduction of their nitro group, with generation of a reactive metabolite or metabolites which interact with DNA leading to a subsequent inhibition of nucleic acid and protein synthesis. Redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs, thereby inhibiting their uptake. On the other hand, redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady-state concentrations of oxygen-derived metabolites that might be of toxicological significance. It seems likely that reduced metabolites of nitroimidazoles (perhaps through covalent binding to tissue macromolecules and/or thiols depletion) are also involved in the nitroimidazoles' toxic effects to animal tissues and in their mutagenic and carcinogenic action.
3-Br J Cancer. 1981 Jul; 44(1): 109–116. (see attached file).
PMCID: PMC2010648
Cytotoxic properties of a 4-nitroimidazole (NSC 38087): a radiosensitizer of hypoxic cells in vitro.
I. J. Stratford, C. Williamson, and C. Hardy
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
5-Phenoxysulphonyl-1-methyl-4-nitroimidazole (NSC 38087) can act as a sensitizer of hypoxic mammalian cells to radiation in vitro. The degree of sensitization achieved is greater than would be predicted from the drug's electron affinity. Cytotoxicity studies have shown that 5 microM NSC 38087 can reduce the surviving fraction of log-phase V79 cells in air at 37 degrees C to 10(-2) after 2 h exposure. This toxicity is considerably increased by small rises in temperature. In contrast to other nitro-heterocyclic radiosensitizers, NSC 38087 and related 5-substituted 4-nitroimidazoles show greater toxicity towards aerobic than to hypoxic cells. Log-phase cells show the highest sensitivity to the toxic action of NSC 38087, with plateau-phase cells, cells with a history of chronic hypoxia, and thermotolerant cells showing greater resistance. These toxicity data are compared to those for the 2-nitroimidazole hypoxic-cell sensitizer misonidazole.
4-Br J Cancer. 1981 Mar; 43(3): 350–354. (see attached file).
PMCID: PMC2010608
Cytotoxicity of metronidazole (Flagyl) and misonidazole (Ro-07-0582): enhancement by lactate.
J. S. Mahood and R. L. Willson
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
The cytotoxic activity of metronidazole (Flagyl) and misonidazole (MISO) to hypoxic Chinese hamster ovary (CHO) cells suspended in standard medium in sealed vials and in gassed spinner flasks has been investigated. Flagyl (5 mM) was only cytotoxic at high initial cell densities. However, when lactate (20 mM) was included in the medium the cytotoxicity of Flagyl at low cell densities was considerable, and similar to that of misonidazole under the same conditions. The relevance of this "lactate effect" to in vivo systems, and the possible mechanisms involved, are discussed.
5-Mechanism of Toxicity of Nitro Compounds (see attached file).
Used in the Chemotherapy of
Trichomoniasis
by Silvia N. J. Moreno* and Roberto Docampo*
The mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin-mediated reduction of their nitro group, with generation of a reactive metabolite or metabolites which interact with DNA leading to a subsequent inhibition of nucleic acid and protein synthesis. Redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs, thereby inhibiting their uptake. On the other hand, redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady-state concentrations of oxygen-derived metabolites that might be of toxicological significance. It seems likely that reduced metabolites of nitroimidazoles (perhaps through covalent binding to tissue macromolecules and/or thiols depletion) are also involved in the nitroimidazoles' toxic effects to animal tissues and in their mutagenic and carcinogenic action
Hoping this will be helpful,
Rafik
Dear Gaurav,
The following papers might be helpful.
1-Br J Cancer. 1984 Feb; 49(2): 215–223. (see attached paper).
PMCID: PMC1976693
Selective toxicity of nitracrine to hypoxic mammalian cells.
W. R. Wilson, W. A. Denny, S. J. Twigden, B. C. Baguley, and J. C. Probert
Copyright and License information ►
Abstract
Hypoxic cells in solid tumours are resistant to ionizing radiation and may be refractory to treatment by many chemotherapeutic agents. For these reasons the identification of drugs with selective toxicity towards hypoxic cells is an important objective in cancer chemotherapy. Nitroimidazoles such as misonidazole demonstrate such hypoxia-selective toxicity but have very low dose potency. The 1-nitroacridine derivative 1-nitro-9-(dimethylaminopropylamino)acridine (nitracrine) binds reversibly to DNA but also forms covalent adducts with DNA in vivo. We have found nitracrine to be selectively toxic to the Chinese hamster ovary cell line AA8 under hypoxic conditions in culture, with a potency approximately 100,000 times higher than that of misonidazole. The effect of oxygen is not a simple dose-modifying one in this system, probably in part because of rapid metabolic inactivation of nitracrine under hypoxic conditions. Viscometric studies with the mini col E1 plasmid PML-21 confirmed that nitracrine binds to DNA by intercalation, and provided an unwinding angle of 16 degrees (relative to 26 degrees for ethidium). It is proposed that the cytotoxicity of nitracrine under hypoxia is due to reductive metabolism to form an alkylating species, but that intercalation of the chromophore may enhance reactivity towards DNA and hence contribute to the marked enhancement of potency with respect to simple nitroheteroaromatic drugs.
2-Environ Health Perspect. 1985 Dec; 64: 199–208. (see attached file).
PMCID: PMC1568619
Research Article
Mechanism of toxicity of nitro compounds used in the chemotherapy of trichomoniasis.
S N Moreno and R Docampo
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
The mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin-mediated reduction of their nitro group, with generation of a reactive metabolite or metabolites which interact with DNA leading to a subsequent inhibition of nucleic acid and protein synthesis. Redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs, thereby inhibiting their uptake. On the other hand, redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady-state concentrations of oxygen-derived metabolites that might be of toxicological significance. It seems likely that reduced metabolites of nitroimidazoles (perhaps through covalent binding to tissue macromolecules and/or thiols depletion) are also involved in the nitroimidazoles' toxic effects to animal tissues and in their mutagenic and carcinogenic action.
3-Br J Cancer. 1981 Jul; 44(1): 109–116. (see attached file).
PMCID: PMC2010648
Cytotoxic properties of a 4-nitroimidazole (NSC 38087): a radiosensitizer of hypoxic cells in vitro.
I. J. Stratford, C. Williamson, and C. Hardy
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
5-Phenoxysulphonyl-1-methyl-4-nitroimidazole (NSC 38087) can act as a sensitizer of hypoxic mammalian cells to radiation in vitro. The degree of sensitization achieved is greater than would be predicted from the drug's electron affinity. Cytotoxicity studies have shown that 5 microM NSC 38087 can reduce the surviving fraction of log-phase V79 cells in air at 37 degrees C to 10(-2) after 2 h exposure. This toxicity is considerably increased by small rises in temperature. In contrast to other nitro-heterocyclic radiosensitizers, NSC 38087 and related 5-substituted 4-nitroimidazoles show greater toxicity towards aerobic than to hypoxic cells. Log-phase cells show the highest sensitivity to the toxic action of NSC 38087, with plateau-phase cells, cells with a history of chronic hypoxia, and thermotolerant cells showing greater resistance. These toxicity data are compared to those for the 2-nitroimidazole hypoxic-cell sensitizer misonidazole.
4-Br J Cancer. 1981 Mar; 43(3): 350–354. (see attached file).
PMCID: PMC2010608
Cytotoxicity of metronidazole (Flagyl) and misonidazole (Ro-07-0582): enhancement by lactate.
J. S. Mahood and R. L. Willson
Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract
The cytotoxic activity of metronidazole (Flagyl) and misonidazole (MISO) to hypoxic Chinese hamster ovary (CHO) cells suspended in standard medium in sealed vials and in gassed spinner flasks has been investigated. Flagyl (5 mM) was only cytotoxic at high initial cell densities. However, when lactate (20 mM) was included in the medium the cytotoxicity of Flagyl at low cell densities was considerable, and similar to that of misonidazole under the same conditions. The relevance of this "lactate effect" to in vivo systems, and the possible mechanisms involved, are discussed.
5-Mechanism of Toxicity of Nitro Compounds (see attached file).
Used in the Chemotherapy of
Trichomoniasis
by Silvia N. J. Moreno* and Roberto Docampo*
The mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin-mediated reduction of their nitro group, with generation of a reactive metabolite or metabolites which interact with DNA leading to a subsequent inhibition of nucleic acid and protein synthesis. Redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs, thereby inhibiting their uptake. On the other hand, redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady-state concentrations of oxygen-derived metabolites that might be of toxicological significance. It seems likely that reduced metabolites of nitroimidazoles (perhaps through covalent binding to tissue macromolecules and/or thiols depletion) are also involved in the nitroimidazoles' toxic effects to animal tissues and in their mutagenic and carcinogenic action
Hoping this will be helpful,
Rafik
Thank you very much, Dear Prof. Rafik, hope the inputs provided by you will surely work within my case.
- Badges
- Science topic