Inhibition of O6-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death
| Autor: | Ralf Schirrmacher, Markus Christmann, Bernd Kaina, Andrea Piee-Staffa, Frank Rösch, Ute Mühlhausen, Regine Garcia Boy |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Methyltransferase
Guanine Antineoplastic Agents Pharmacology Biology DNA methyltransferase Nitrosourea Compounds O(6)-Methylguanine-DNA Methyltransferase chemistry.chemical_compound Organophosphorus Compounds In vivo Temozolomide medicine Humans Enzyme Inhibitors neoplasms chemistry.chemical_classification Cell Death digestive system diseases In vitro Dacarbazine Glucose Enzyme Biochemistry chemistry Molecular Medicine Fotemustine HeLa Cells medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 311:585-593 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.104.071316 |
| Popis: | The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is an important suicide enzyme involved in the defense against O(6)-alkylating mutagens. It also plays a role in the resistance of tumors to anticancer drugs targeting the O(6)-position of guanine, such as temozolomide and fotemustine. Several potent MGMT inhibitors have been developed sensitizing cells to O(6)-alkylating agents. Aimed at targeting MGMT inhibitors to tumor cells, we synthesized MGMT inhibitory compounds conjugated with glucose to improve uptake in tumor cells. Here, we compared O(6)-benzylguanine, O(6)-2-fluoropyridinylmethylguanine (O(6)FPG), O(6)-3-iodobenzylguanine, O(6)-4-bromothenylguanine, and O(6)-5-iodothenylguanine with the corresponding C8-linker beta-d-glucose derivatives. All glucose conjugated inhibitors were 3- to 5-fold less effective than the corresponding nonconjugated drugs as to MGMT inhibition that was measured in cell extracts (in vitro) and cultivated HeLaS3 cells (in vivo). Except for O(6)FPG, IC(50) values of the guanine derivatives applied in vitro and in vivo were correlated. A similar correlation was not obvious for the corresponding glucosides, indicating differences in cellular uptake. C8-alpha-d-glucosides were less effective than beta-glucosides. From the newly developed glucose-conjugated inhibitors tested, O(6)-4-bromothenylguanine-C8-beta-d-glucoside (O(6)BTG-C8-betaGlu) was most potent in inhibiting MGMT both in vitro and in vivo. At a concentration of 0.1 microM, it inhibited cellular MGMT to completion. It was not toxic, even when applied chronically to cells at high dose (up to 20 microM). O(6)BTG-C8-betaGlu strongly potentiated the killing effect of fotemustine and temozolomide, causing reversal from MGMT+ to MGMT- phenotype. Therefore, O(6)BTG-C8-betaGlu seems to be especially suitable for approaching MGMT inhibitor targeting in tumor therapy. |
| Databáze: | OpenAIRE |
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