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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Institute of Toxicology, University of Mainz, Mainz, Germany (B.K., A.P.-S., M.C.); Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany (U.M., F.R., R.S.); and Research Group Epigenetics, Deutsches Krebsforschungszentrum, Heidelberg, Germany (R.G.B.)

The DNA repair protein O⁶-methylguanine-DNA methyltransferase (MGMT) is an important suicide enzyme involved in the defense against O⁶-alkylating mutagens. It also plays a role in the resistance of tumors to anticancer drugs targeting the O⁶-position of guanine, such as temozolomide and fotemustine. Several potent MGMT inhibitors have been developed sensitizing cells to O⁶-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 O⁶-benzylguanine, O⁶-2-fluoropyridinylmethylguanine (O⁶FPG), O⁶-3-iodobenzylguanine, O⁶-4-bromothenylguanine, and O⁶-5-iodothenylguanine with the corresponding C8-linker -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 O⁶FPG, IC₅₀ 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--D-glucosides were less effective than -glucosides. From the newly developed glucose-conjugated inhibitors tested, O⁶-4-bromothenylguanine-C8--D-glucoside (O⁶BTG-C8-Glu) was most potent in inhibiting MGMT both in vitro and in vivo. At a concentration of 0.1 µM, it inhibited cellular MGMT to completion. It was not toxic, even when applied chronically to cells at high dose (up to 20 µM). O⁶BTG-C8-Glu strongly potentiated the killing effect of fotemustine and temozolomide, causing reversal from MGMT+ to MGMT– phenotype. Therefore, O⁶BTG-C8-Glu seems to be especially suitable for approaching MGMT inhibitor targeting in tumor therapy.

Address correspondence to: Dr. Bernd Kaina, Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany. E-mail: kaina{at}uni-mainz.de

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