2-Chloroacetaldehyde, a metabolite of cyclophosphamide in the rat

Shaw, Ian C.; Graham, M.I.; McLean, A. E. M.

doi:10.3109/00498258309052281

Cited by 20 publications

(4 citation statements)

References 8 publications

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“…As dechloroethylation involves removal of one chloroethyl sidechain, the appearance of N-dechloroethylcyclophosphamide should be accompanied by the appearance of 2-chloroacetaldehyde. Recently, Shaw et a1 [25] have demonstrated the presence of 2-chloroacetaldehyde as a CP metabolite in the urine of rats given intravenous doses of 14C-CP. Because 2-chloroacetaldehyde is highly reactive, these authors postulate that 2-chloroacetaldehyde, like AC, might be responsible for some of the side effects associated with CP chemotherapy.…”

Section: Role Of Metabolites In Cp Antitumor Effectsmentioning

confidence: 99%

Cyclophosphamide teratogenesis: A review

Mirkes

1985

Teratog Carcinog Mutagen

180

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Cyclophosphamide (CP) is one of the best studied teratogens; it produces primarily central nervous system and skeletal anomalies in rats, mice, rabbits, monkeys, and humans. Furthermore, CP is one of the most extensively studied antineoplastic agents. Recent work using in vitro rodent embryo culture has demonstrated that CP must be bioactivated to be teratogenic. This finding extends earlier work showing that CP must be activated to achieve its antineoplastic and mutagenic effects. Activation of CP to its teratogenic, mutagenic, and antineoplastic form is mediated by microsomal cytochrome P-450 monooxygenases, which convert CP to 4-hydroxycyclophosphamide (4OHCP). In the absence of detoxification, 4OHCP spontaneously breaks down to phosphoramide mustard (PM) and acrolein (AC). PM is the CP metabolite believed to be responsible for the antineoplastic and mutagenic effects of CP, whereas AC is thought to cause the side effects associated with CP chemotherapy. Recent work has shown that the teratogenic effects of CP are mediated by both PM and AC. Although it is far from proven, available evidence supports the hypothesis that DNA is the primary target in terms of the teratogenic, mutagenic, and antineoplastic effects of CP. Although the nature of the DNA lesions produced by CP, which are responsible for its teratogenic, mutagenic, and antineoplastic effects, is not completely understood, cross-linking of DNA seems to play a critical role in the antineoplastic properties of CP. Preliminary information obtained from embryos exposed to CP metabolites suggests that, although DNA cross-linking might play a role in CP teratogenesis, metabolite-induced DNA strand breakage and/or induction of mutations might also play a role. Although insights into the molecular mechanisms underlying CP teratogenesis are just beginning to accumulate, the availability of in vitro embryo culture combined with the modern armamentarium of molecular biology will allow teratologists to probe further the molecular aspects of teratogenesis.

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Section: Role Of Metabolites In Cp Antitumor Effectsmentioning

confidence: 99%

Cyclophosphamide teratogenesis: A review

Mirkes

1985

Teratog Carcinog Mutagen

180

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“…Chloroacetaldehyde (CAA) is a potent mutagen, capable of impairing an array of normal cellular functions [1–3]. It is a reactive metabolite of many industrial chemicals [4, 5]and of the alkylating, cytostatic drugs ifosfamide (IFO) and cyclophosphamide [6, 7]. CAA is presumed to be neurotoxic [8–10], and its presence is thought to potentiate IFO associated encephalopathies.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of respiration by methylene blue in rat liver mitochondria

1997

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The effect of methylene blue on isolated rat liver mitochondria in the presence and absence of chloroacetaldehyde was investigated. Fatty acid oxidation was inhibited by chloroacetaldehyde and subsequently stimulated by methylene blue. Assessment of tightly coupled mitochondria revealed decreasing respiratory control ratios induced by increasing concentrations of methylene blue and methylene blue provoked mitochondrial swelling. In uncoupled mitochondria, methylene blue promoted a concentration-dependent stimulation of respiration. These findings provide evidence that methylene blue, the redox dye currently used as an antidote for encephalopathy associated with alkylating chemotherapy, uncouples oxidative phosphorylation and acts as an electron transfer mediator to stimulate mitochondrial respiration.© 1997 Federation of European Biochemical Societies.

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“…The 4-ketocyclophosphamide (32) was obtained from bis(2chloroethyl)amine (Hill et al, 1970). The metabolite 2-chloroacetaldehyde (38) was synthesized from 2-chloroacetic acid (Shaw et al, 1983).…”

Section: Synthesis Of Ctx (3) Metabolitesmentioning

confidence: 99%

The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

Hrynchak

Sousa

Pinto

et al. 2017

Drug Metabolism Reviews

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Anticancer drugs are presently guarantying more survivors as a result of more powerful drugs or combinations of drugs used in therapy. Thus, it has become more crucial to study and overcome the side effects of these therapies. Cardiotoxicity is one of the most relevant side effects on the long-term cancer survivors, because of its high social and economic impact. Drug metabolism can result in active metabolites or toxic metabolites that can lead to important side effects. The metabolites of anticancer drugs are possible culprits of cardiotoxicity; however, the cardiotoxicity of many of the metabolites in several drug classes was not yet suitably studied so far. On the other hand, the use of prodrugs that are bioactivated through metabolism can be a good alternative to obtain more cardio safe drugs. In this review, the methods to obtain and study metabolites are summarized and their application to the study of a group of anticancer drugs with acknowledged cardiotoxicity is highlighted. In this group of drugs, doxorubicin (DOX, 1), mitoxantrone (MTX, 2), cyclophosphamide (CTX, 3) and 5-fluorouracil (5-FU, 4) are included, as well as the tyrosine kinase inhibitors, such as imatinib (5), sunitinib (6) and sorafenib (7). Only with the synthesis and purification of considerable amounts of the metabolites can reliable studies be performed, either in vitro or in vivo that allow accurate conclusions regarding the cardiotoxicity of anticancer drug metabolites and then pharmacological prevention or treatment of the cardiac side effects can be done.

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2-Chloroacetaldehyde, a metabolite of cyclophosphamide in the rat

Cited by 20 publications

References 8 publications

Cyclophosphamide teratogenesis: A review

Cyclophosphamide teratogenesis: A review

Stimulation of respiration by methylene blue in rat liver mitochondria

The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

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