Antibody-mediated transduction of p53 selectively kills cancer cells.
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.
Weisbart
Richard H
RH
Division of Rheumatology, Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System, Sepulveda, CA 91343, USA. rweisbar@ucla.edu
Hansen
James E
JE
Chan
Grace
G
Wakelin
Rika
R
Chang
Sophia S
SS
Heinze
Emil
E
Miller
Carl W
CW
Koeffler
Phillip H
PH
Yang
Fusheng
F
Cole
Greg M
GM
Min
Yoon S
YS
Nishimura
Robert N
RN
D000917:Antibody Formation; D016923:Cell Death; D018076:DNA, Complementary; D015316:Genetic Therapy; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology; D008222:Lymphokines; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D012795:Sialoglycoproteins; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology*
D018076:DNA, Complementary; C089422:Fv protein, human; D007128:Immunoglobulin Fragments; D008222:Lymphokines; D012795:Sialoglycoproteins; D016159:Tumor Suppressor Protein p53