p21WAF1/CIP1 antisense therapy radiosensitizes human colon cancer by converting growth arrest to apoptosis.
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 (approximately 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.
Tian
H
H
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007-2197, USA.
Wittmack
E K
EK
Jorgensen
T J
TJ
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002455:Cell Division / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D005260:Female; D016193:G1 Phase / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016376:Oligonucleotides, Antisense; D011838:Radiation-Sensitizing Agents