Metabolism of hydrazine anti-cancer agents

Tweedie, Donald J.; Erikson, John M.; Prough, Russell A.

doi:10.1016/0163-7258(87)90095-7

Cited by 27 publications

(8 citation statements)

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“…Procarbazine is used to treat a number of cancers, including Hodgkin's lymphoma. Metabolites of this drug inhibit DNA polymerase and react directly with DNA (35). Human single doses do not exceed 150 mg/m 2 (23); the equivalent mouse dose for this drug is f50 mg/kg.…”

Section: Resultsmentioning

confidence: 99%

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

2008

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Understanding and estimating the genetic hazards of exposure to chemical mutagens and anticancer drugs in humans requires the development of efficient systems for monitoring germ line mutation. The suitability of a single-molecule PCRbased approach for monitoring mutation induction at the mouse expanded simple tandem repeat (ESTR) locus Ms6-hm by chemical mutagens and anticancer drugs has been validated. The frequency of ESTR mutation was evaluated in the germ line of male mice exposed to the well-characterized alkylating agent and mutagen, ethylnitrosourea, and four widely used anticancer drugs, bleomycin, cyclophosphamide, mitomycin C, and procarbazine. The dose-response of ethylnitrosourea-induced mutation was found to be very close to that previously established using a pedigree-based approach for ESTR mutation detection. Paternal exposure to the clinically relevant doses of bleomycin (15-30 mg/kg), cyclophosphamide (40-80 mg/kg), and mitomycin C (2.5-5 mg/kg) led to statistically significant, dose-dependent increases in ESTR mutation frequencies in the germ line of treated male mice. Exposure to procarbazine led to a maximal increase in mutation frequency at 50 mg/kg, with a plateau at the higher concentrations. The results of this study show that the singlemolecule PCR technique provides a new and efficient experimental system for monitoring the genetic effects of anticancer drugs, capable of detecting increases in mutation rates at clinically relevant doses of exposure. In addition, this approach dramatically reduces the number of mice needed for the measurement of germ line mutation induction.

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Section: Resultsmentioning

confidence: 99%

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

2008

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“…One explanation for the differences in O 2 /CO sensitivity is that the hydrazine intermediates formed by azo group reduction may have differential sensitivity to reoxidation by molecular oxygen to the azo intermediate or alternatively, they are not sensitive and are reduced to primary amines. We have shown that hydrazines are easily oxidized by cytochromes P450 and are sensitive to metal-catalyzed oxidation (Prough et al, 1981;Tweedie et al, 1987). The mechanism accounting for the oxygen sensitivity or insensitivity remains unsolved.…”

Section: Commentarymentioning

confidence: 99%

Aldehyde Reduction by Cytochrome P450

2011

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This protocol describes the procedure for measuring the relative rates of metabolism of the α,β-unsaturated aldehydes, 9-anthracene aldehyde (9-AA) and 4-hydroxy-trans-2-nonenal (4-HNE); specifically the aldehyde reduction reactions of cytochrome P450s (CYPs). These assays can be performed using either liver microsomal or other tissue fractions, spherosome preparations of recombinant CYPs, or recombinant CYPs from other sources. The method used here to study the reduction of a model α,β-unsaturated aldehyde, 9-AA, by CYPs was adapted from the assay used to investigate 9-anthracene oxidation as reported by Marini et al. (Marini et al., 2003). For experiments measuring reduction of the endogenous aldehyde, 4-HNE, the substrate was incubated with CYP in the presence of oxygen and NADPH and the metabolites were separated by High Pressure Liquid Chromatograpy (HPLC), using an adaptation of the method of Srivastava et al. (Srivastava et al., 2010). For study of 9-AA and 4-HNE reduction, the first step involves incubation of the substrate with the CYP in appropriate media, followed by quantification of metabolites through either spectrofluorimetry or analysis by HPLC coupled with a radiometric assay, respectively. Metabolite identification can be achieved by HPLC GC-mass spectrometric analysis. Inhibitors of cytochrome P450 function can be utilized to show the role of the hemoprotein or other enzymes in these reduction reactions. The reduction reactions for CYP’s were not inhibited by either anaerobiosis or inclusion of CO in the gaseous phase of the reaction mixture. These character of these reactions are similar to those reported for some cytochrome P450-catalyzed azo reduction reactions.

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“…4.87). Hydrazines also undergo one-electron oxidations but the intermediates are short-lived and these pathways are less well defined (154). The two-electron oxidation pathway is shown in Figure 4.87.…”

Section: Oxidation Of Heteroatomsmentioning

confidence: 99%

Drug Metabolism

Uetrecht¹,

Trager²

2007

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Metabolism of hydrazine anti-cancer agents

Cited by 27 publications

References 60 publications

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice

Aldehyde Reduction by Cytochrome P450

Drug Metabolism

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