Cholecystokinin (CCK) is an important trophic
hormone for the pancreas, and
CCK receptors are present on
pancreatic carcinoma cells. We sought to determine whether either CCK itself or an antagonist of CCK could modulate the sensitivity of the human pancreatic cell line MIA-PaCa2 to
cisplatin (DDP). The IC50 for a 1-h exposure to DDP was 35.3 +/- 3.2(SD) microM. Exposure to CCK8 octapeptide at physiologic and supra-physiologic concentrations did not alter the sensitivity of MIA-PaCa2 cells to DDP. The
CCK receptor antagonist
MK-329 was directly cytotoxic to the MIA-PaCa2 cells on a constant exposure schedule with an IC50 of 9.5 +/- 1.4 (SD) microM.
MK-329 enhanced the sensitivity of MIA-PaCa2 cells to DDP by
a factor of 3.5, and the interaction between DDP and
MK-329 was shown to be synergistic by median-effect analysis. At a level of 50% cell kill, the combination index was 0.58 +/- 0.10. The ability of
MK-329 to sensitize cells to DDP was schedule-dependent and required prolonged exposure to the antagonist following a 1-h exposure to DDP.
MK-329 had no effect on the uptake of a radiolabeled analog of
cisplatin ([3H]-dichloro(
ethylenediamine)
platinum) and did not affect intracellular
glutathione content.
MK-329 had no effect on the cell-cycle-phase distribution of MIA-PaCa2 cells and did not alter the DDP-induced cell-cycle perturbations. The cytotoxic effect of
MK-329 and its ability to interact synergistically with DDP could not be reversed by CCK. We conclude that
MK-329 is directly cytotoxic to
pancreatic carcinoma cells and can enhance their sensitivity to DDP by a mechanism not related to its ability to antagonize the
CCK receptor.