Blockage of abasic site repair enhances antitumor efficacy of 1,3-bis-(2-chloroethyl)-1-nitrosourea in colon tumor xenografts.
Methoxyamine (MX) has been shown to potentiate the antitumor effect of temozolomide (TMZ) in human tumor xenograft models. This potentiation is due to the reactivity of MX with apurinic/pyrimidinic (AP) sites in DNA, which are formed following DNA glycosylase removal of TMZ-induced methyl-purine adducts. MX-bound AP sites cannot be further processed by base excision repair (BER), resulting in cell death. On the basis of this finding, we investigated in vivo whether MX enhanced therapeutic efficacy of other agents, such as 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) that generates AP sites during DNA repair. Nude mice carrying human colon tumor xenografts, HCT116 and HCT116-Ch3, were treated by a single injection (i.p) of BCNU alone (30 mg/kg) or MX (2 mg/kg) combined with BCNU. The effect on tumor growth of BCNU alone was very moderate. Combined administration of MX and BCNU produced significant inhibition of tumor growth. Tumor growth delays were 14 +/- 3 days in HCT116 and 16 +/- 2 days in HCT116-Ch3 tumors, respectively (P < 0.05 versus control or BCNU alone groups). Similar results were also observed in SW480 and DLD1 tumors. Importantly, no systemic toxicity was noted with BCNU and MX. In contrast, BCNU (at dose of 25 mg/kg) combined with O(6)-benzylguanine (BG), an inhibitor of O(6)-alkylguanine-DNA alkyltransferase (AGT) being tested in clinical trials, caused toxic death in all treated mice. However, a lower dose BCNU (10 mg/kg) combined with BG and MX had significant antitumor effect without toxic death. Thus, targeting BER with MX is a promising strategy to improve the antitumor activity of BCNU and perhaps other DNA-damaging agents.
Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. LxL32@po.cwru.edu
Lili
L
Liu
Ling
L
Yan
Jon R
JR
Donze
Stanton L
SL
Gerson
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002330:Carmustine / Q000627:therapeutic use*; D002455:Cell Division; D003110:Colonic Neoplasms / Q000188:drug therapy*; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine