Does acrolein contribute to the cytotoxicity of cyclophosphamide?

Wrabetz, E.; Peter, G.; Hohorst, H. J.

doi:10.1007/bf00405956

Cited by 28 publications

(9 citation statements)

References 7 publications

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“…The possibility of such a sensitising action has been suggested by Alarcon and Meienhofer (1971) for acrolein, but no supporting evidence has been presented. In agreement with previous findings (Brock, 1976;Wrabetz et al, 1980), we have also demonstrated the relative lack of toxicity of acrolein ( Figure 4a). Thus, deschloro-4-hydroperoxycyclophosphamide, which has its bis-(P-chloroethyl)amine group replaced by diethylamine, produced acrolein (Alarcon & Meienhofer, 1971) and depleted cellular GSH as efficiently as 4-OOH-CP (Figure 4b), but was non-cytotoxic because it cannot give rise to PM (Figure 4a).…”

Section: Effects Of Cellular Gsh Content On the Alkylating Capacity Osupporting

confidence: 93%

Glutathione diminishes the anti-tumour activity of 4-hydroperoxycyclophosphamide by stabilising its spontaneous breakdown to alkylating metabolites

Lee

1991

Br J Cancer

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There is considerable evidence that glutathione (GSH) plays a major role in protecting tumour cells against the cytotoxicity of the oxazaphosphorines, including cyclophosphamide (CP) and its active congener, 4-hydroperoxycyclophosphamide (4-OOH-CP), both in vitro (Russo et al., 1986; Crook et al., 1986a) and in vivo (Gurtoo et al., 1981;Carmichael et al., 1986b; Ono & Shrieve, 1987). Recently, in a study of 17 tumour cell lines, we noted a close correlation between the chemosensitivity of these cell lines to 4-OOH-CP and their steady-state GSH level (Lee et al., 1990). It was further noted that whilst GSH 'detoxifies' 4-OOH-CP, 4-OOH-CP in turn depletes GSH. In fact, 4-OOH-CP is at toxic concentrations a potent depletor of cellular GSH. Most important, the tumour cell GSH depletion and the lethality produced by 4-OOH-CP appear to be linked events. Significant 4-OOH-CP cytotoxicity was invariably associated with GSH depletion, and vice versa. In the present paper, evidence is presented showing that GSH modulates the cytotoxicity of 4-OOH-CP by participating in chemical reactions at three separate locations in the metabolic pathway of 4-OH-CP, its spontaneous breakdown product. (4-OOH-CP gives rise rapidly to 4-OH-CP following dissolution without any enzymic involvement and may be regarded as equivalent to 4-OH-CP pharmacologically (Sladek, 1987). 4-OOH-CP is the preferred 'activated' cyclophosphamide for routine use only because of its higher stability in crystalline state and easier synthesis.) 4-OH-CP, sometimes called 'activated' cyclophosphamide, is formed from the hydroxylation of CP by the hepatic mixed-function oxidases (Figure 1). 4-OH-CP is in reality the 'transport' form of CP since it is in this form that active CP reaches the target tumour cells (Sladek, 1987). Intracellular 4-OH-CP is in equilibrium with its ring-opened tautomer aldophosphamide (AP). The fate of AP may follow one of three main competing metabolic pathways: (1) spontaneous fission to acrolein (AC) and phosphoramide mustard (PM), (2) ring-closure and hydroxylation to produce once again the parent 4-OH-CP. As depicted in Figure 1, glutathione (GSH) can participate in conjugative reactions at three separate locations that may have considerable influence on the eventual cytotoxicity of 4-OH-CP. (1) Reaction with AP as described above which shifts the pseudoequilibrium between 4-OH-CP and AP in favour of the former and thereby curtails the spontaneous degradation of AP to toxic metabolites. GSH also reacts irreversibly with the toxic metabolites AC and PM, but particularly the former (2 and 3) (Gurtoo et al., 1981). In the accompanying paper we demonstrated that when the combined rates of the conjugation reactions exceed the rate of GSH recovery, i.e. when GSH is being depleted, significant cytotoxicity inevitably occurs. The present findings suggest that GSH depletion impacts directly on the cytotoxic potency of 4-OH-CP by destabilising AP (see Figure 1)

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Section: Effects Of Cellular Gsh Content On the Alkylating Capacity Osupporting

confidence: 93%

Glutathione diminishes the anti-tumour activity of 4-hydroperoxycyclophosphamide by stabilising its spontaneous breakdown to alkylating metabolites

Lee

1991

Br J Cancer

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“…Because AC is a well known cytotoxic agent [17-191, several investigators have attempted to elucidate what role, if any, AC plays in the antitumor properties of CP. Using an analog of CP (4-hydroperoxydechlorocyclophosphamide), which releases AC but not an alkylating species (PM), Wrabetz et a1 [18] were able to show that AC generated by the metabolism of CP did not contribute to the cytotoxic (antineoplastic) activity of CP. Moreover, they pointed out that, although AC itself was cytotoxic, the mechanism of cytotoxicity of "extracellular" AC differed from that produced by CP.…”

Section: Role Of Metabolites In Cp Antitumor Effectsmentioning

confidence: 99%

“…In order to corroborate these findings, Mirkes et al [73] took another approach. They exposed embryos in vitro to dechlorocyclophosphamide (D-CP), which is metabolized in a manner similar to CP [74,75] and forms AC but not PM. Using this derivative of CP it was possible to expose embryos to AC without the simultaneous exposure to PM.…”

Section: Cp Teratogenesis In Vltro Role Of Cp Metabolitesmentioning

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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“…[14] With the new approach, locally produced acrolein should have a much reduced side effect on other organs. The pharmacological properties of prodrug 13 are currently under investigation.…”

Section: Resultsmentioning

confidence: 99%