p21(WAF1/CIP1) Antisense therapy radiosensitizes human colon cancer by converting growth arrest to apoptosis

Substantial evidence suggests that loss of cellular p21(WAF1/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.