The p53 tumor suppressor gene in anticancer agent-induced apoptosis and chemosensitivity of human gastrointestinal cancer cell lines

Purpose: While the target of many anticancer agents has been identified, th e processes leading to killing of the cancer cells and the molecular basis of resistance to the drugs are not well understood. We used human gastroint estinal cancer cell lines and examined how anticancer agents induced cell k illing and how the chemosensitivity of these lines was determined. Methods: Twelve gastrointestinal cancer cell lines were examined for the presence o f either a wild-type or mutant p53 gene by direct sequencing. We also deter mined whether or not cell killing would occur when the cell lines were expo sed to anticancer drugs. The sensitivity to the anticancer agents was deter mined based on colony formation. Results, All 12 gastrointestinal cancer ce ll lines carried either a wild-type or mutant p53 gene. Three lines, MKN45, MKN74 and COLO320, carried the wild-type p53 gene, and nine carried the mu tant p53 gene. When three lines were exposed to the anticancer agents etopo side, doxorubicin (DXR) or 5-fluorouracil (5-FU), cell death ensued. In the se cells, the population of cells in G(1) phase increased after exposure to high-dose anticancer agents, but cells in GZ phase increased when exposed to low-dose anticancer agents. Our observations support the concept that ce lls carrying the wild-type p53 gene tend to be sensitive to etoposide and D XR and, in particular, deletion of the p53 function results in a greater re sistance to anticancer agents. Conclusion: Based on our findings, human gas trointestinal cancer-related cell death apparently occurs via a p53-depende nt pathway. A relationship was observed between the induction of cell death and chemosensitivity.