Abstract
Pancreatic cancer is one of the most devastating malignant tumors and the development of an effective novel modality of treatment is awaited.
We studied the mechanism of growth-inhibition of 5-fluorouracil (5-FU) on human pancreatic cancer cells focusing on p53 status and expression of bcl-2 family genes. COLO-357 cells with wild-type p53 gene and T3M4, Panc-1 and AsPC-1 cells with mutant p53 gene were used. Growth of COLO-357 and T3M4 cells was inhibited by the treatment with relatively low concentrations of 5-FU, and growths of Panc-1 cells was suppressed by treatment with relatively high concentrations of 5-FU under serum-supplemented conditions. In contrast, 5-FU had no effect on growth of AsPC-1 cells. While DNA fragmentation in COLO-357 cells was induced by a low concentration of 5-FU and then declined with higher concentrations of 5-FU, in T3M4 cells DNA fragmentation was gradually induced with increasing concentrations of 5-FU. Expression of bax mRNA and protein was enhanced by 5-FU in COLO-357 cells. Although expression of bc1XS mRNA was enhanced by 5-FU in both COLO-357 and T3M4 cells, Bc1XS protein was not detected on Western blotting. Increased expression of bax was associated with increased inhibition of cell growth by 5-FU in pancreatic cancer cells with a wild-type p53 gene and bc1XS may play a role in the growth-inhibitory effect of 5-FU on pancreatic cancer cells both with wild-type and mutant p53 genes. Therefore, gene-therapy targeting Bc1X for pancreatic cancer may be effective. AsPC-1 cells provide a useful tool for the study of mechanisms of resistance to chemotherapy.
