The DNA-repair
protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a decisive determinant of resistance of
tumor cells to methylating and chloroethylating anti-
cancer drugs. Therefore, selective inhibition of MGMT in
tumors is expected to cause
tumor sensitization. Several inhibitors of MGMT have been developed which function in both
tumors and normal tissue. To deplete MGMT preferentially in
tumors, strategies to target the inhibitor to the
tumor tissue need to be developed. Here, we report on the properties of
glucose-conjugated MGMT inhibitors that might be useful for
tumor targeting since
tumor cells frequently over-express
glucose transporter.
O(6)-Benzylguanine (O6BG), 8-aza-O(6)-benzylguanine, O(6)-(4-bromothenyl)-guanine (O6BTG) and the corresponding spacer-linked
beta-D-glucose conjugates were analyzed comparatively for MGMT-inhibitory activity. Substitution at the N9 position of the
purine moiety resulted generally in a reduction in the efficiency with which the inhibitors blocked MGMT. However, the inhibitory activity of the O6BTG conjugates increased with increasing spacer length, and O6BTG conjugated with a C8 spacer with
beta-D-glucose was nearly as effective as O6BTG on its own. MGMT was inhibited by the conjugates both in crude
cell extracts and upon treatment of intact HeLa cells, indicating efficient uptake of the
glucose conjugates into cells. Since the O6BTG-C8-D-glucose conjugate 8-[O(6)-(4-bromothenyl)-guan-9-yl]-
octyl-beta-D-glucoside was highly efficient at MGMT inhibition in a non-toxic concentration range, the
drug might be a useful tool for specific
tumor sensitization.