In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 9, No. 2 ( 2010-02-01), p. 450-460
Kurzfassung:
E1B-55kD-deleted adenoviruses have been used as conditionally replicative adenoviruses (CRAds) for therapeutic purposes in tumors with loss-of-function p53 mutation. To target cancer cells that harbor activating mutant KRAS (KRASaMut) but spare p53wild normal cells, we constructed and examined by reporter assays a KRASaMut but not p53-responsive promoter, the Δp53REP2 promoter. The Δp53REP2 promoter, derived from human double minute 2 (hdm2) P2 promoter with its p53 response elements being deleted, was used to regulate the expression of the hdm2 transgene in a novel E1B-55kD-deleted CRAd, the Ad-KRhdm2. The Ad-KRhdm2 selectively replicated in and exerted cytopathic effects on KRASaMut colorectal cancer cell lines (HCT116, LoVo, LS174T, LS123, and SW620), regardless of their p53 gene statuses, by forming plaques and exhibiting cytopathic effect in cultured cells. Ad-KRhdm2, like other E1B-55kD-deleted adenoviruses, also exerted selective cytopathic effects on tumor cells with loss-of-function p53 mutant. The multiplicities of infection of Ad-KRhdm2 required to decrease 50% viability of KRASaMut tumor cells cultured for 7 days were 440 to 3,400 times less than those of MRC5 normal fibroblasts and KRASwild/p53wild RKO tumor cells. Intratumoral injection of Ad-KRhdm2 vectors exhibited specific lytic activities in nude mouse xenografts of KRASaMut cell lines (LoVo, SW620, and LS174T) but not in xenografts of RKO cells. Transduction of KRASaMut/p53wild HCT116, LoVo, and LS174T cells by Ad-KRhdm2 significantly increased Hdm2 expression, decreased p53 level, and abolished the p53-transactivating p21Cip1 promoter activity. Ad-KRhdm2 has shown its therapeutic potential in KRASaMut cancer cells and warrants further clinical trials. Mol Cancer Ther; 9(2); 450–60
Materialart:
Online-Ressource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.MCT-09-0704
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2010
ZDB Id:
2062135-8
SSG:
12
