Zelluläre Effekte von Irinotecan auf colorectale Carcinomzellen sind vom p53 Status abhängig

Abstract

Irinotecan (CPT-11) is superior to 5-FU/folinic acid in patients with metastatic colorectal cancer (CRC). We analysed the sensitivity and the cellular mechanisms of CPT-11 in CRC cells related to their p53 status. An isogeneic cell model (HCT116 p53^+/+ and p53^−/−) and 4 other p53-mutated and 3 p53-wildtype cell lines were treated for 48 h with 2 nM SN-38, the active metabolite of CPT-11. MTT, clonogenic assay, FACS cell cycle analyses, cell death detection ELISA and PARP-Western blot were performed. After two days in MTT more HCT116 p53^−/− cells died, whereas in clonogenic assay after 12 d no difference was obvious. p53^+/+ cells showed a longterm G2/M arrest, while p53−/− cells exhibited only shortterm G2/M arrest, followed by apoptosis. Clonogenic assay of all cell lines showed a superior response in p53^+/+ cells. These data indicate that CPT-11 sensitivity and cellular effects in CRC cells are p53 dependent.