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Experimental Therapeutics |
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University Medical Center, Washington, D.C. 20007-2197
Substantial evidence suggests that loss of cellular
p21WAF1/CIP1 results in increased apoptotic killing by
ionizing radiation. We hypothesized that a p21 antisense (AS)
oligodeoxynucleotide (ODN) could be used to sensitize cancer cells to
radiotherapy. In vitro treatment of colon cancer cells
(HCT116/p21+/+) with p21 AS ODN (200 nM) led to
inhibition of radiation-induced p21 expression (>95% inhibition,
0–30 Gy), resulting in a loss of G1 arrest and an
enhancement of apoptosis to comparable levels and with similar kinetics
to HCT116/p21-/- cells (
60% apoptotic cells at
96 h after 10 Gy). In vivo, p21 AS ODN in combination
with radiation (i.p. ODN for 6 days at 20 mg/kg/day and 15 Gy)
increased apoptosis in s.c. p21+/+ tumors in nude mice to
levels similar to those of p21-/- tumors (2-fold at
24 h postirradiation) and improved radiocurability of
p21+/+ tumors to levels comparable to those of
p21-/- tumors (p21+/+, two of eight cures
versus p21-/-, two of nine cures). Our
findings suggest that p21 AS treatment may be a rational approach to
improve conventional radiotherapy outcomes.
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