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Vol. 57, Issue 3, 503-511, March 2000
Cancer Research Campaign Centre for Cancer Therapeutics,
Institute of Cancer Research, Sutton, Surrey, United Kingdom
Wild-type p53 is frequently mutated in late-stage ovarian cancer and
has been proposed as a determinant of cisplatin chemosensitivity. We
have therefore established a human ovarian cancer cell line differing
only in p53 status and characterized its response after treatment with
different platinum complexes. The wild-type p53-expressing cell line
A2780 was stably transfected with HPV-16 E6 (E6) or an
empty vector (VC) as control. Parental A2780 and 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- to 3-fold
more sensitive to transplatin and the novel cisplatin analog ZD0473
than VC, whereas the trans-platinum analog JM335 was approximately equitoxic. Platinum uptake was similar for all of the
cell lines after cisplatin. The removal of platinum-DNA adducts, as
measured by atomic absorption spectroscopy, was reduced in E6 compared
with VC after cisplatin but similar after JM335. After 10 µM
cisplatin, the G1 population (0-96 h) was reduced in E6
cells compared with VC, whereas the S phase (8-48 h) and G2 phase (48-96 h) were increased. Similar proportions of
VC and E6 cells died by apoptosis, as detected by annexin V binding, but more E6 cells died by necrosis relative to VC. Our results suggest
that the loss of functional p53 can increase cisplatin cytotoxicity in
A2780, with loss of G1/S checkpoint control and decreased
cisplatin-DNA adduct repair, but these effects can be circumvented by
the use of JM335, which forms different DNA-platinum adducts.
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