Effect of p53 status on sensitivity to platinum complexes in a human ovarian cancer cell line

Wild-type p53 is frequently mutated in late-stage ovarian cancer and has be en proposed as a determinant of cisplatin chemosensitivity. We have therefo re established a human ovarian cancer cell line differing only in p53 statu s and characterized its response after treatment with different platinum co mplexes. The wild-type p53-expressing cell line A2780 was stably transfecte d with HPV-16 E6 (E6) or an empty vector (VC) as control. Parental A2780 an d VC had similar cisplatin sensitivities, whereas E6 was 3- to 4-fold more sensitive as measured by sulforhodamine B and clonogenic assay. E6 was 2- t o 3-fold more sensitive to transplatin and the novel cisplatin analog ZD047 3 than VC, whereas the trans-platinum analog JM335 was approximately equito xic. Platinum uptake was similar for all of the cell lines after cisplatin. The removal of platinum-DNA adducts, as measured by atomic absorption spec troscopy, was reduced in E6 compared with VC after cisplatin but similar af ter JM335. After 10 mu M cisplatin, the G(1) population (0-96 h) was reduce d in E6 cells compared with VC, whereas the S phase (8-48 h) and G(2) phase (48-96 h) were increased. Similar proportions of VC and E6 cells died by a poptosis, as detected by annexin V binding, but more E6 cells died by necro sis relative to VC. Our results suggest that the loss of functional p53 can increase cisplatin cytotoxicity in A2780, with loss of G(1)/S checkpoint c ontrol and decreased cisplatin-DNA adduct repair, but these effects can be circumvented by the use of JM335, which forms different DNA-platinum adduct s.