O(6)-methylguanine-DNA methyltransferase (MGMT) as a determinant of resistance to camptothecin derivatives.
The precise mechanisms of resistance to camptothecin (CPT)-derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O(6)-methylguanine-DNA methyltransferase (MGMT), participated in resistance to irinotecan hydrochloride (CPT-11), its active metabolite SN-38, and a novel CPT derivative, DX-8951f. In 17 human cancer cell lines, MGMT gene expression level closely correlated with sensitivity to the CPT derivatives, and inhibition of MGMT activity by nontoxic 5 microM O(6)-benzylguanine augmented the drug activity in relation to the MGMT expression levels in 8 cell lines examined. Transfection of pCR / MGMT-sense into U-251MG and pCR / MGMT-antisense into T98G and HEC-46 cells revealed that increased MGMT expression decreased the sensitivity to CPT-11, SN-38, and DX-8951f, whereas repressed MGMT expression sensitized cells to the drugs. Western analysis revealed that treatment of MGMT-expressing T98G cells with the drugs caused a decrease of both MGMT and topo I in a dose-dependent manner. Although, in the transfectants, MGMT expression did not so closely correlate with the sensitivity to drugs as to nimustine hydrochloride (ACNU), MGMT is probably an important resistance determinant to CPT derivatives, and may play some role in the topo I-mediated DNA damage and / or the repair process.
Okamoto
Ryo
R
Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
Takano
Hiroshi
H
Okamura
Tatsunori
T
Park
Ji-Seon
JS
Tanimoto
Keiji
K
Sekikawa
Takashi
T
Yamamoto
Wataru
W
Sparreboom
Alex
A
Verweij
Jaap
J
Nishiyama
Masahiko
M
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004341:Drug Evaluation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005978:Glutathione; C095887:exatecan; D002166:Camptothecin