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.