Circadian variation inO6-alkylguanine-DNA alkyltransferase activity in circulating blood mononuclear cells of healthy human subjects

Marchenay, C.; Cellarier, Eric; Lévi, Françis; Rolhion, Christine; Kwiatkowski, Fabrice; Bruno, Claudio; Madelmont, Jean‐Claude; Chollet, Philippe

doi:10.1002/1097-0215(20010101)91:1<60::aid-ijc1010>3.0.co;2-n

Cited by 19 publications

(18 citation statements)

References 36 publications

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“…As glucocorticoids are involved in the regulation of various physiological functions, such as energy metabolism and immunity function, 24-h changes in circulating glucocorticoid levels also affect the efficacy of many drugs Kuramoto et al, 2006). It has been reported that glucocorticoids can induce the expression of the MGMT gene in human cell lines (Marchenay et al, 2001). In this study, we also confirmed the induction of the mouse MGMT gene in response to glucocorticoid stimuli.…”

supporting

confidence: 81%

“…The rhythmic change in the activity of MGMT seems to be the underlying cause of the dosing time-dependent change in DTIC-induced hepatotoxicity. Time-dependent variations in MGMT activity are also observed in human circulating mononuclear cells (Marchenay et al, 2001), indicating the possibility that varying MGMT activity also affects DTIC toxicity in humans. Our results will provide a clue to understanding how the rhythmic change in hepatic MGMT activity affects the hepatotoxicity induced by the alkylating agent DTIC.…”

Section: Discussionmentioning

confidence: 98%

“…Glucocorticoids exert their action on gene expression though the activation of cytoplasmic glucocorticoid receptors that bind to glucocorticoid response elements (GREs) on DNA. Two putative GREs have been identified in the human MGMT promoter (Marchenay et al, 2001). The distance between the two GREs is approximately 20 bp, and they are located 1.0 kilobase pair upstream of the putative transcription start site; however, the promoter architecture of the mouse MGMT gene has been poorly characterized to date.…”

Section: Discussionmentioning

confidence: 99%

“…dependent variations in MGMT activity are also observed in human circulating mononuclear cells (Marchenay et al, 2001), suggesting that the time-dependent change in MGMT activity affects the toxicity of alkylating agents; however, the exact regulation mechanism of circadian oscillation of MGMT activity remains to be clarified.…”

mentioning

confidence: 99%

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Glucocorticoid-Dependent Expression ofO⁶-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

Horiguchi

Kim

Matsumoto³

et al. 2010

J Pharmacol Exp Ther

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O 6-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against the alkylating agent-induced cytotoxic lesion O 6 -alkylguanine in DNA. Although a significant circadian variation in MGMT activity has been found in the liver of mice, the exact mechanism of the variation remains poorly understood. In this study, we present evidence that glucocorticoids were required for the 24-h oscillation of MGMT expression in mouse liver. The exposure of mouse hepatic cells (Hepa1-6) to dexamethasone (DEX) significantly increased the mRNA levels of MGMT in a dose-dependent manner. The DEX-induced increase in MGMT expression was reversed by concomitant treatment with RU486 [11␤- [p-(dimethylamino) phenyl]-17␤-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one], a glucocorticoid receptor antagonist. The mRNA levels of MGMT and its enzymatic activity in the liver of mice showed significant 24-h oscillations, which were not observed in adrenalectomized mice. A single administration of DEX to adrenalectomized mice significantly increased the mRNA levels of MGMT in the liver. These findings suggest that the 24-h oscillation in the hepatic expression of MGMT is caused by the endogenous rhythm of glucocorticoid secretion. Dacarbazine (DTIC), a potent O 6 -guanine-alkylating agent, causes serious hepatotoxicity accompanied by hepatocellular necrosis and hepatic vein thrombosis. DTIC-induced hepatotoxicity in mice was attenuated by administering the drug at the time of day when MGMT expression was abundant. The present findings suggest that glucocorticoid-regulated oscillation in the hepatic MGMT expression is the underlying cause of dosing timedependent changes in DTIC-induced hepatotoxicity.Cytotoxic alkylating agents, cystemustine, dacarbazine (DTIC), and temozolomide, are highly effective against lymphatic and several types of solid tumor (Marchesi et al., 2007). They damage DNA by forming adducts with bases, the most common of which occur at the N 7 position of guanine and the N 3 position of adenine, which are repaired by the base excision repair mechanism. On the other hand, another important lesion formed, in terms of mutagenesis and cytotoxicity, is O 6 -alkylguanine (Marchesi et al., 2007). This adduct can be removed by O 6 -methylguanine-DNA methyltransferase (MGMT), which thus plays a key role in DNA repair from O 6 -guanine-alkylating agent exposure (Kaina et al., 2007). In fact, the lethal effect of DTIC in homozygous MGMT knockout mice was more severe than it was in wildtype mice (Shiraishi et al., 2000).It has been reported that MGMT activity in the liver of mice shows significant circadian variation, and this rhythmicity could account for the dosing time-dependent change in cystemustine-induced toxicity (mortality and myelosuppression) in mice (Martineau-Pivoteau et al., 1996a,b). Time-

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supporting

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Glucocorticoid-Dependent Expression ofO⁶-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

Horiguchi

Kim

Matsumoto³

et al. 2010

J Pharmacol Exp Ther

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“…The AGT assay was performed on protein extracts of M4Beu cells treated in vitro by IBgBZ, using a previously described procedure (Marchenay et al, 2001). Increasing amounts of M4Beu cell protein extracts were incubated with [ 3 H]Nmethyl-N-nitrosourea-methylated calf thymus DNA substrate for 1 h at 37°C.…”

Section: Drugs [mentioning

confidence: 99%

A New O⁶-Alkylguanine-DNA Alkyltransferase Inhibitor Associated with a Nitrosourea (Cystemustine) Validates a Strategy of Melanoma-Targeted Therapy in Murine B16 and Human-Resistant M4Beu Melanoma Xenograft Models

Rapp

Maurizis²,

Papon³

et al. 2008

J Pharmacol Exp Ther

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Chemoresistance to O6 -alkylating agents is a major barrier to successful treatment of melanoma. It is mainly due to a DNA repair suicide protein, O 6 -alkylguanine-DNA alkyltransferase (AGT). Although AGT inactivation is a powerful clinical strategy for restoring tumor chemosensitivity, it was limited by increased toxicity to nontumoral cells resulting from a lack of tumor selectivity. Achieving enhanced chemosensitization via AGT inhibition preferably in the tumor should protect normal tissue. To this end, we have developed a strategy to target AGT inhibitors.In this study, we tested a new potential melanoma-directed AGT inhibitor [2-amino-6-(4-iodobenzyloxy)-9-[4-(diethylamino) ethylcarbamoylbenzyl] purine; IBgBZ] designed as a conjugate of O 6 -(4-iododbenzyl)guanine (IBg) as the AGT inactivator and a N,N-diethylaminoethylenebenzamido (BZ) moiety as the carrier to the malignant melanocytes. IBgBZ demonstrated AGT inactivation ability and potentiation of O 6 -alkylating agents (cystemustine, a chloroethylnitrosourea) in M4Beu highly chemoresistant human melanoma cells both in vitro and in tumor models. The biodisposition study on mice bearing B16 melanoma, the standard model for the evaluation of melanomadirected agents, and the secondary ion mass spectrometry imaging confirmed the concentration of IBgBZ in the tumor and in particular in the intracytoplasmic melanosomes. These results validate the potential of IBgBZ as a new, more tumorselective, AGT inhibitor in a strategy of melanoma-targeted therapy.

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Updates in IDH-Wildtype Glioblastoma

et al. 2022

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Glioblastoma is the most aggressive primary brain tumor with a poor prognosis. The 2021 WHO CNS5 classification has further stressed the importance of molecular signatures in diagnosis although therapeutic breakthroughs are still lacking. In this review article, updates on the current and novel therapies in IDH-wildtype GBM will be discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-022-01251-6.

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Circadian variation inO6-alkylguanine-DNA alkyltransferase activity in circulating blood mononuclear cells of healthy human subjects

Cited by 19 publications

References 36 publications

Glucocorticoid-Dependent Expression ofO⁶-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

Glucocorticoid-Dependent Expression ofO⁶-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

A New O⁶-Alkylguanine-DNA Alkyltransferase Inhibitor Associated with a Nitrosourea (Cystemustine) Validates a Strategy of Melanoma-Targeted Therapy in Murine B16 and Human-Resistant M4Beu Melanoma Xenograft Models

Updates in IDH-Wildtype Glioblastoma

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Circadian variation inO6-alkylguanine-DNA alkyltransferase activity in circulating blood mononuclear cells of healthy human subjects

Cited by 19 publications

References 36 publications

Glucocorticoid-Dependent Expression ofO6-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

Glucocorticoid-Dependent Expression ofO6-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

A New O6-Alkylguanine-DNA Alkyltransferase Inhibitor Associated with a Nitrosourea (Cystemustine) Validates a Strategy of Melanoma-Targeted Therapy in Murine B16 and Human-Resistant M4Beu Melanoma Xenograft Models

Updates in IDH-Wildtype Glioblastoma

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Glucocorticoid-Dependent Expression ofO⁶-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

Glucocorticoid-Dependent Expression ofO⁶-Methylguanine-DNA Methyltransferase Gene Modulates Dacarbazine-Induced Hepatotoxicity in Mice

A New O⁶-Alkylguanine-DNA Alkyltransferase Inhibitor Associated with a Nitrosourea (Cystemustine) Validates a Strategy of Melanoma-Targeted Therapy in Murine B16 and Human-Resistant M4Beu Melanoma Xenograft Models