title: Certain imidazotetrazines escape O6-methylguanine-DNA methyltransferase and mismatch repair.
abstract: Resistance to temozolomide (TMZ), conferred by O6-methylguanine-DNA methyltransferase (MGMT) or mismatch repair (MMR) deficiency, presents obstacles to successful glioblastoma multiforme (GBM) treatment. Activities of novel TMZ analogs, designed to overcome resistance, were tested against isogenic SNB19 and U373 GBM cell lines (V = vector control, low MGMT; M = MGMT overexpression). TMZ and triazene MTIC demonstrated >9-fold resistance in SNB19M cells (cf SNB19V). N-3 methyl ester analog 11 and corresponding triazene 12 inhibited growth of TMZ-sensitive (V) and TMZ-resistant (M) cells (GI(50) <50 μM). Ethyl ester 13 and triazene 14 gave similar profiles. MMR-deficient colorectal carcinoma cells, resistant to TMZ (GI(50) >500 μM), responded to analog 11 and 13 treatment. Cross-resistance to these agents was not observed in cell lines possessing acquired TMZ resistance (SNB19VR; U373VR). Methyl ester 11 blocked SNB19V, SNB19M and SNB19VR cells in S and G(2)/M, causing dose- and time-dependent apoptosis. DNA damage, recruiting excision repair was detected by alkaline comet assay; H2AX phosphorylation indicated a lethal DNA double-strand break formation following analog 11 exposure. Compounds 11 and 13 demonstrated 3.7- and 5.1-fold enhanced activity in base excision repair-deficient Chinese hamster ovary cells; furthermore, poly (ADP-ribose) polymerase-1 inhibition potentiated HCT-116 cells' sensitivity to analog 11. In conclusion, analogs 11 and 13 exert anticancer activity irrespective of MGMT and MMR.
authors: Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
authors: Jihong
authors: J
authors: Zhang
authors: Malcolm F G
authors: MF
authors: Stevens
authors: Marc
authors: M
authors: Hummersone
authors: Srinivasan
authors: S
authors: Madhusudan
authors: Charles A
authors: CA
authors: Laughton
authors: Tracey D
authors: TD
authors: Bradshaw
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D053843:DNA Mismatch Repair / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D010865:Pilot Projects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D007093:Imidazoles; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide