EFFICACY OF P53 ADENOVIRUS-MEDIATED GENE-THERAPY AGAINST HUMAN BREAST-CANCER XENOGRAFTS

In response to DNA damage, p53 protein accumulates in the cell nucleus causing cells to undergo DNA repair or apoptosis, programmed cell dea th. Reintroduction of wild-type p53 into tumors with null or mutant p5 3 offers a novel strategy for controlling tumor growth, by inducing ap optotic death in neoplastic cells. The efficacy of a replication-defic ient p53 adenovirus construct was tested against three human breast ca ncer cell lines expressing mutant p53, MDA-MB-231, -468, and -435. 231 and 468 cells were both highly transduced at a multiplicity of infect ion of 10. By contrast, 435 cells were rarely transduced. p53 adenovir us-mediated gene therapy was highly effective against 231 and 468 tumo r xenografts in nude mice. At a total dose of 2.2 x 10(9) cellular inf ectious units (CIU), inhibition of 231 tumor growth was 86% (P less th an or equal to.01). Thirty-seven percent of that growth inhibition was due to p53, while 49% was adenovirus-specific. Inhibition of 468 tumo r growth was 74% (P less than or equal to.001). Forty-five percent of that inhibition was p53-specific, while 28% was adenovirus-specific. T he ED(50) values for 231 and 468 tumor growth inhibition were 3 x 10(8 ) CIU and 2 x 10(8) CIU, respectively. Injection of p53 Ad into 231 or 468 tumors induced apoptosis. By contrast, growth inhibition in 435 t umors treated with p53 adenovirus was not significant, probably due to low adenovirus transduction. 231 and 435 cells both expressed high le vels of alpha(1), beta(1), beta(3), and beta(5) integrin subunits, rul ing out lack of the appropriate integrins as the reason for the low in fection rate in 435 cells. Our results demonstrate the ability of wild -type p53 to curtail cancerous cell growth in vivo in tumors expressin g mutant p53. The ability of beta-gal Ad to infect tumor cells in vitr o was generally predictive of in vivo p53 Ad efficacy.