Chloroacetaldehyde: mode of antitumor action of the ifosfamide metabolite

Brüggemann, Svenja K.; Radike, Kerstin; Braasch, Kirsten; Hinrichs, Jürgen; Kisro, Jens; Hagenah, Wibke; Peters, Stefan O.; Wagner, Thomas

doi:10.1007/s00280-005-0061-0

Cited by 27 publications

(20 citation statements)

References 35 publications

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“…6A). This mode of action may explain previous observations indicating that CAA depleted cellular reduced glutathione and ATP, disturbed Ca 2+ signaling, lipid peroxidation, and, ultimately, cell necrosis and death (8,(35)(36)(37)(38)(39). The cytotoxic effect of CAA is likely due to low or no reactivity with MESNA (Fig.…”

Section: Discussionsupporting

confidence: 49%

“…In addition to the curtailment of ATP synthesis, dysfunction of C-I may lead to elevated production of superoxide radicals, causing mitochondrial DNA mutations, lipid peroxidation, and protein denaturation (35)(36)(37)(38). The current study shows that the IFOinduced inhibition of NADH:oxidoreductase was associated with a significant elevation of [NADH], inhibition of the flux through the PDH reaction, and incorporation of acetyl-CoA (derived from pyruvate) into the TCA cycle (Figs.…”

Section: Discussionmentioning

confidence: 69%

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Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and B-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 69%

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

et al. 2006

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“…Although the semimustard products of dealkylation are not themselves able to cross-link DNA and thus have low cytotoxic potency , the other dealkylation products are reactive aldehydes. Thus, dealkylation of oxazaphosphorine mustards forms chloroacetaldehyde, which has been reported to cross-link DNA (Spengler and Singer, 1988), induce DNA breaks, and inhibit DNA synthesis (Brüggemann et al, 2006). Chloroacetaldehyde is a potent cytotoxin in vitro (Brüggemann et al, 1997), shows antitumor activity in vivo (Börner et al, 2000), is neurotoxic (Goren et al, 1986;Lewis and Meanwell, 1990), is nephrotoxic (Skinner et al, 1993), and is considered to contribute to the clinical toxicity of oxazaphosphorine mustards (Zhang et al, 2005a).…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans

Atwell²,

Wilson

2009

Drug Metab Dispos

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ABSTRACT:PR-104 is the phosphate ester of a 3,5-dinitrobenzamide nitrogen mustard (PR-104A) that is reduced to active hydroxylamine and amine metabolites by reductases in tumors. In this study, we evaluate the excretion of [ 3 H]PR-104 in mice and determine its metabolite profile in mice, rats, dogs, and humans after a single intravenous dose. Total radioactivity was rapidly and quantitatively excreted in mice, with cumulative excretion of 46% in urine and 50% in feces. The major urinary metabolites in mice were products from oxidative N-dealkylation and/or glutathione conjugation of the nitrogen mustard moiety, including subsequent mercapturic acid pathway metabolites. A similar metabolite profile was seen in mouse bile, mouse plasma, and rat urine and plasma. Dogs and humans also showed extensive thiol conjugation but little evidence of N-dealkylation. Humans, like rodents, showed appreciable reduced metabolites in plasma, but concentrations of the cytotoxic amine metabolite (PR-104M) were higher in mice than humans. The most conspicuous difference in metabolite profile was the much more extensive O-␤-glucuronidation of PR-104A in dogs and humans than in rodents. The structure of the O-␤-glucuronide (PR-104G) was confirmed by independent synthesis. Its urinary excretion was responsible for 13 ؎ 2% of total dose in humans but only 0.8 ؎ 0.1% in mice. Based on these metabolite profiles, biotransformation of PR-104 in rodents is markedly different from that in humans, suggesting that rodents may not be appropriate for modeling human biotransformation and toxicology of PR-104.

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“…An equimolar amount of chloroacetaldehyde (CAA, 10) is formed in each of these N-dealkylation reactions. This metabolite is known to be responsible for both nephrotoxicity and neurotoxicity, which may be associated with IFO treatment (Boddy and Yule, 2000;Chatton et al, 2001;Ajithkumar et al, 2007), even if it has been recently reported that CAA could contribute to IFO cytotoxicity (Brü ggemann et al, 2006). Reducing CAA formation may reduce frequency of IFO-related neurotoxicity and nephrotoxicity.…”

mentioning

confidence: 99%

New Ifosfamide Analogs Designed for Lower Associated Neurotoxicity and Nephrotoxicity with Modified Alkylating Kinetics Leading to Enhanced in Vitro Anticancer Activity

Storme

Deroussent²,

Mercier³

et al. 2008

J Pharmacol Exp Ther

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Ifosfamide is a well known prodrug for cancer treatment with cytochrome P450 metabolism. It is associated with both antitumor activity and toxicities. Isophosphoramide mustard is the bisalkylating active metabolite, and acrolein is a urotoxic side product. Because acrolein toxicity is limited by coadministration of sodium mercaptoethanesulfonate, the incidence of urotoxicity has been lowered. Current evidence suggests that chloroacetaldehyde, a side-chain oxidation metabolite, is responsible for neurotoxicity and nephrotoxicity. The aim of our research is to prevent chloroacetaldehyde formation using new enantioselectively synthesized ifosfamide analogs, i.e., C7,C9-dimethyl-ifosfamide. We hypothesize that reduced toxicogenic catabolism may induce less toxicity without changing anticancer activity. Metabolite determinations of the dimethyl-ifosfamide analogs were performed using liquid chromatography and tandem mass spectrometry after in vitro biotransformation by drug-induced rat liver microsomes and human microsomes expressing the main CYP3A4 and minor CYP2B6 enzymes. Both human and rat microsomes incubations produced the same N-deschloroalkylated and 4-hydroxylated metabolites. A coculture assay of 9L rat glioblastoma cells and rat microsomes was performed to evaluate their cytotoxicity. Finally, a mechanistic study using 31 P NMR kinetics allowed estimating the alkylating activity of the modified mustards. The results showed that C7,C9-dimethyl-ifosfamide exhibited increased activities, although they were still metabolized through the same N-deschloroalkylation pathway. Analogs were 4 to 6 times more cytotoxic than ifosfamide on 9L cells, and the generated dimethylated mustards were 28 times faster alkylating agents than ifosfamide mustards. Among these new ifosfamide analogs, the 7S,9R-enantiomer will be assessed for further in vivo investigations for its anticancer activity and its toxicological profile.The bisalkylating agent ifosfamide (IFO) was introduced into clinical trials in the 1970s, but its early use was limited by severe urotoxicity resulting in hemorrhagic cystitis. This side effect led to the development of sodium mercaptoethanesulfonate associated with hydration as a safe and effective regional uroprotection. Further studies have demonstrated IFO activity against a wide range of tumor types, from soft tissue sarcomas to lymphomas both in adult and pediatric

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Chloroacetaldehyde: mode of antitumor action of the ifosfamide metabolite

Cited by 27 publications

References 35 publications

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Ifosfamide-Induced Nephrotoxicity: Mechanism and Prevention

Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans

New Ifosfamide Analogs Designed for Lower Associated Neurotoxicity and Nephrotoxicity with Modified Alkylating Kinetics Leading to Enhanced in Vitro Anticancer Activity

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