Inhibition of <i>O</i><sup>6</sup>-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death

Kaina, Bernd; Mühlhausen, Ute; Piée-Staffa, Andrea; Christmann, Markus; Boy, Regine García; Rösch, Frank; Schirrmacher, Ralf

doi:10.1124/jpet.104.071316

Cited by 52 publications

(39 citation statements)

References 36 publications

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“…3) inactivated MGMT in cell extracts and in living cells in the sequence: 6 -iodothenylguanine, and the same order of potency was seen with the corresponding glucose conjugates. O 6 -(2-fluropyridimylmethl)guanine-C8-b-D-glucose was significantly less effective than the other inactivators [53]. The conjugates were not cytotoxic per se in cell culture, penetrated quickly into living cells and depleted MGMT within *45 min (unpublished data).…”

Section: Mgmt Inhibitor Targetingmentioning

confidence: 99%

“…3). This is about 10 times more potent than O 6 -BG with an IC 50 of 3.4 nM compared to 180 nM for O 6 -BG [52]; in vivo, an IC 50 for O 6 -BTG of 4 nM and for O 6 -BG of 35 nM was reported for HeLa S3 cells [53]. These agents are discussed extensively below.…”

Section: Mgmt Inhibitorsmentioning

confidence: 99%

“…The conjugates were not cytotoxic per se in cell culture, penetrated quickly into living cells and depleted MGMT within *45 min (unpublished data). When given 1 h prior to and after treatment with the alkylating agent, O 6 -BTG-C8-b-D-glucose was similar to O 6 -BTG in its ability to sensitise MGMT-expressing CHO and HeLa cells to fotemustine and temozolomide toxicity in colony formation experiments [53].…”

Section: Mgmt Inhibitor Targetingmentioning

confidence: 99%

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Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Kaina

Margison

Christmann

2010

Cell. Mol. Life Sci.

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126

116

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O (6)-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O (6)-methylguanine and O (6)-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O (6)-benzylguanine and O (6)-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.

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Section: Mgmt Inhibitor Targetingmentioning

confidence: 99%

Section: Mgmt Inhibitorsmentioning

confidence: 99%

Section: Mgmt Inhibitor Targetingmentioning

confidence: 99%

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Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Kaina

Margison

Christmann

2010

Cell. Mol. Life Sci.

Self Cite

126

116

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“…Finally, in contrast to the situation with BCNU, there may be other alkylating agents that can be administered at full dose along with O 6 BG, without an increase in toxicity to normal tissues. AGT inhibition has been shown to potentiate Temozolomide activity in vitro and in vivo (22), and Temozolomide is active in melanoma. In one ongoing clinical trial in primary brain tumor patients, Temozolomide is being administered in combination with O 6 BG.…”

mentioning

confidence: 99%

Phase II Trial of the O6-Alkylguanine DNA Alkyltransferase Inhibitor O6-Benzylguanine and 1,3-Bis(2-Chloroethyl)-1-Nitrosourea in Advanced Melanoma

Gajewski

Sosman

Gerson

et al. 2005

Clinical Cancer Research

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Purpose: 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) induces DNA damage via a chloroethyl adduct at the O 6 position of guanine, which can be repaired by O 6 -alkylguanine DNA alkyltransferase (AGT) expressed in melanoma. We postulated that the addition of O 6 benzylguanine (O 6 BG), a potent inactivator of AGT, would improve the clinical response to BCNU in melanoma. Experimental Design: Patients had measurable disease, adequate organ function, and a corrected Diffusing capacity of the lung for carbon monoxide (DLCO) of z70% predicted. They were accrued into two cohorts based on prior chemotherapy. O BG to analyze AGT depletion. Treatment was every 6 weeks, and clinical response was assessed after every two cycles. Results: Forty-two patients were enrolled, 22 of these patients were chemotherapy-naïve. In the chemotherapy-naïve cohort, there was a patient with a complete response (CR), 4 with stable disease (SD), 13 with progressive disease (PD), and 4 nonevaluable patients; the median time to progression was 80 days and the median survival was 211days. In the prior-chemotherapy cohort, there were no responses, 3 SD, 15 PD, and 2 nonevaluable patients; median time to progression was 54 days and median survival was 120 days. AGTwas depleted from PBMC in the 15 patients tested. Grades 3 to 4 myelosuppression was seen in 57% of patients; toxicities were similar between the two cohorts. Conclusions: O 6 BG/BCNU was successfully administered on an outpatient basis and depleted AGT from PBMC. However, significant myelosuppression was observed and the clinical outcome was not improved. Alternative mechanisms of resistance to melanoma cell death need to be investigated.The incidence of malignant melanoma is steadily increasing.More than 59,000 new cases and >10,000 deaths were estimated in 2004 (up from 54,000 and 7,600, respectively, in 2003). Dacarbazine and interleukin 2 remain the only Food and Drug Administration-approved drugs for metastatic melanoma, each with response rates of f15%. Clearly, more effective therapeutic approaches are needed. Several alkylating agents are active in melanoma, including Temozolomide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the overall response rates are z15%, and combination chemotherapy has not been shown to be superior to the single agent dacarbazine (1). These results suggest that mechanisms of chemotherapy resistance are dominant in this disease, which has prompted continued research to uncover treatable mechanisms of melanoma escape from the actions of cytotoxic chemotherapy.It has been shown that BCNU induces its cytotoxic effect largely through the generation of a chlorethyl adduct at the O 6 -position of guanine in DNA that subsequently undergoes an intramolecular rearrangement to produce an unstable ethanoguanine intermediate, which subsequently reacts with cytosine on the opposite DNA strand (2, 3). An N 1 -guanine-N 3 -cytosine-ethanol cross-link results. Development of the interstrand cross-links can be prevented by the DNA repair p...

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“…New generations of AGT inhibitors with improved tumor selectivity have also been developed (Juillerat and Juillerat-Jeannerat, 2007). They were designed as conjugates of a first-generation AGT inhibitor (Bg, BTg, and 2-amino-O 4 -benzylpteridine) and a ligand of a high-expression, tumor-specific receptor or transporter (D-glucose, glucuronic acid, and folic acid) (Kaina et al, 2004;Nelson et al, 2004;Wei et al, 2005). Finally, to date, none of these conjugation approaches has demonstrated any successful in vivo tumor selectivity.…”

Section: Discussionmentioning

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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Inhibition of O⁶-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death

Cited by 52 publications

References 36 publications

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Phase II Trial of the O6-Alkylguanine DNA Alkyltransferase Inhibitor O6-Benzylguanine and 1,3-Bis(2-Chloroethyl)-1-Nitrosourea in Advanced Melanoma

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

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Inhibition of O6-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death

Cited by 52 publications

References 36 publications

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Targeting O 6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Phase II Trial of the O6-Alkylguanine DNA Alkyltransferase Inhibitor O6-Benzylguanine and 1,3-Bis(2-Chloroethyl)-1-Nitrosourea in Advanced Melanoma

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

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Resources

About

Inhibition of O⁶-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death

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