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p53
status determines the cell fate of glioblastoma cells in response to SN-38
Yinglin
Wang, Linda M. Liau, Timothy F. Cloughesy, Paul S. Mischel
UCLA,
Los Angeles, CA
The
camptothecin derivative CPT-11, a topoisomerase I inhibitor, has impressive
activity against glioblastoma cells in vitro and in xenografts.
In early clinical trials, a subset of glioblastoma patients showed a good
clinical response, but the molecular parameters that determine sensitivity to
the drug have yet to be determined.
p53 is not thought to affect cellular sensitivity to the drug.
However, we hypothesized that p53 may play a critical role in determining the
type of response initiated by CPT-11 mediated DNA damage.
To test this hypothesis, we transduced HPV E6 into glioblastoma cells to
abrogate p53 function and assessed cellular responses to SN-38 (the active
metabolite of CPT-11).
Here we show that p53 did not alter the overall sensitivity of glioblastoma
cells to SN-38, but had a dramatic effect on the cellular response of tumor
cells to the drug.
A clinically achievable dose of SN-38, 20ng/ml, caused prolonged G2/M arrest and
induced markers of cellular senescence in p53-wild type cells.
In contrast, SN-38 caused apoptosis of the p53-deficient cells, as measured by
both flow cytometric and biochemical approaches.
To extend these observations to a biologically relevant model, we analyzed
response in two low passage primary cultures of different p53 status derived
from glioblastoma biopsies.
The p53-wild-type cells underwent G2/M arrest, while the p53-deficient cells
became apoptotic.
Most importantly, p53-wild type tumor cells, both U87MG and patient derived
cultures, were able to resume proliferation after 14 days of SN-38 treatment
when re-cultured in drug-free medium.
In contrast, the E6 expressing U87MG cells and the p53-deficient primary
glioblastoma cells did not regrow after drug withdrawal.
These results demonstrate that p53 has a dramatic effect on how glioblastoma
cells process SN-38-mediated DNA damage, and suggests that CPT-11 should be
targeted to glioblastoma patients whose tumors are p53-deficient.
Copyright © 2003 American Association for Cancer Research. All rights reserved.
Source: http://aacr03.agora.com/planner/displayabstract.asp?presentationid=6450
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