Suppression of breast cancer growth and angiogenesis by an antisense oligodeoxynucleotide to p21(Waf1/Cip1).
Under some conditions, p21(Waf1/Cip1) plays an assembly factor role for the cyclins and cyclin-dependent kinases, and recent reports demonstrate that p21 can act as an anti-apoptotic protein. Thus, it is logical to exploit this function of p21 as an anti-cancer target. We have performed a pilot study showing that daily subcutaneous injection of a phosphorothioate antisense p21 oligodeoxynucleotide, which we have previously shown to attenuate p21 levels in vitro, into nude mice who have been implanted with highly metastatic breast cancer cells results in inhibition of tumor growth and angiogenesis. Inhibition of in vitro endothelial capillary formation confirms that these oligodeoxynucleotides have a direct effect upon tumor angiogenesis. The attractiveness of our novel approach to breast cancer therapy, which capitalizes on the anti-apoptotic function of p21, derives from the ease of transfection of antisense oligodeoxynucleotides as well as the observations that p21(-/-) mice do not develop spontaneous tumors, making techniques exploiting the assembly factor and anti-apoptotic role of p21 worthy of further study against breast cancer.
Weiss
Robert H
RH
Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616, USA. rhweiss@ucdavis.edu
Marshall
Debbie
D
Howard
Laura
L
Corbacho
Ana M
AM
Cheung
Anthony T
AT
Sawai
Earl T
ET
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000098:blood supply / Q000628:therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010865:Pilot Projects; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016376:Oligonucleotides, Antisense