Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O6-Methylguanine-DNA methyltransferase with O6-benzylguanine or O6-benzyl-2'-deoxyguanosine.
Adenocarcinoma of the pancreas is refractory to chemotherapeutic agents, including BCNU and streptozotocin. We have previously shown that drugs, which adduct the O(6)- position of guanine, are ineffective against pancreatic tumor cell lines because of high expression of O(6)-methylguanine-DNA methyltransferase (MGMT). The effect of MGMT inactivation on the resistance of pancreatic tumors to carmustine (BCNU) and to temozolomide (TMZ) was examined in five human pancreatic tumor xenografts in athymic mice. Tumor-bearing mice were treated: (a) with a single i.p. injection of BCNU or TMZ at the maximum-tolerated doses of 75 and 340 mg/m(2), respectively; and (b) with O(6)-benzylguanine (BG) or O(6)-benzyl-2'-deoxyguanosine (dBG) in combination with BCNU or TMZ. Pretreatment with the MGMT inactivators BG or dBG reduced the maximum-tolerated doses of BCNU and TMZ to 35 and 170 mg/m(2), respectively. MIA PaCa-2, CFPAC-1, PANC-1, CAPAN-2, and BxPC-3 having MGMT levels of 890, 1680, 680, 900, and 330 fmol/mg protein, respectively, were unresponsive to BCNU. MIA PaCa-2 and CFPAC-1 were also unresponsive to TMZ, whereas CAPAN-2 responded with a tumor delay of 32 days. BG or dBG sensitized all tumors to both BCNU and TMZ. BG plus BCNU treatment of MIA PaCa-2, CFPAC-1, PANC-1, CAPAN-2, and BxPC-3 induced tumor delays of 18, 16, 12, 14, and 16 days, respectively. In comparison, dBG plus BCNU at doses that were equitoxic to BCNU plus BG yielded tumor delays of 30, 19, 16, 21, and 22 days, respectively. The pancreatic tumors tested displayed functional mismatch repair that, however, may not be always sufficiently restrictive to prevent mutations under alkylation stress. Treatments with either BCNU or TMZ resulted in some degree of mutation in recurring tumors with the exception of CAPAN-2, the only wt-p53 xenograft. dBG, a weak MGMT inactivator in vitro as compared with BG, was markedly more effective than the latter in enhancing the efficacy of BCNU against pancreatic tumor xenografts. Both BG and dBG also enhanced the efficacy of TMZ against pancreatic tumors, possibly because of the repression of MGMT, which cannot be achieved with TMZ treatments alone. These results suggest that pancreatic tumors, which are resistant to DNA alkylating agents, may be sensitized to such agents when pretreated with MGMT inactivators.
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000077204:Temozolomide; D013997:Time Factors
D000477:Alkylating Agents; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; C088636:O(6)-benzyl-2'-deoxyguanosine; D006147:Guanine; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003849:Deoxyguanosine; D002330:Carmustine; D000077204:Temozolomide