Antibody-mediated transduction of p53 selectively kills cancer cells.
Weisbart RH,
Hansen JE,
Chan G,
Wakelin R,
Chang SS,
Heinze E,
Miller CW,
Koeffler PH,
Yang F,
Cole GM,
Min YS,
Nishimura RN.
Division of Rheumatology, Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System, Sepulveda, CA 91343, USA. rweisbar@ucla.edu
Some human cancers are caused by functional defects in p53 that are restored by gene therapy with wild-type p53. To circumvent the use of viral vectors, we reconstituted cancer cell lines with p53 by protein transduction. A fusion protein was produced from cDNA constructed from the Fv fragment of an antibody that penetrates living cells and wild-type p53 (Fv-p53). Fv-p53 penetrated and killed cancer cells that do not express p53. Additionally, Fv-p53 killed cancer cells that were malignant as a result of mutations within p53, nuclear exclusion of p53 and over-expression of MDM2. Non-specific toxicity was excluded by showing that Fv-p53 penetrated but did not kill primary cells and cancer cells unresponsive to p53. Fv fragments alone were not cytotoxic, indicating that killing was due to transduction of p53. Fv-p53 was shown to penetrate cancer cells engrafted in vivo. These results support continued efforts to evaluate the potential efficacy of Fv-p53 for the treatment of certain cancers in vivo.
PMID: 15547728 [PubMed - indexed for MEDLINE]