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Potential efficacy of p16 gene therapy for EBV‐positive nasopharyngeal carcinoma
Author(s) -
Li Anna Aihua,
Ng Emily,
Shi Wei,
Lee Andrew,
Chia Marie,
Liu TaJen,
Huang Dolly,
O'Sullivan Brian,
Gullane Pat,
Liu FeiFei
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20065
Subject(s) - nasopharyngeal carcinoma , cancer research , cell cycle , retinoblastoma protein , biology , genetic enhancement , cell cycle checkpoint , apoptosis , cell , immunology , radiation therapy , medicine , gene , biochemistry , genetics
The p16 cell cycle inhibitory gene is a potentially critical molecular abnormality in nasopharyngeal carcinoma (NPC). Its expression is silenced through either deletion or promoter methylation in the vast majority of NPC. This in turn is associated with absent or reduced protein expression, which has been previously demonstrated by our group to correlate with inferior clinical outcome. Therefore, we were interested in evaluating the potential of adenoviral mediated p16 gene therapy (adv. p16 ) in an EBV‐positive NPC model (C666‐1). We confirm that under basal conditions, p16 protein is undetectable in C666‐1 cells, which, in turn, is associated with retention of retinoblastoma protein (pRb) expression. P16 expression was observed as early as 4 hr after infection of C666‐1 cells with adv. p16 (10 pfu/cell) with no discernible perturbation in pRb for up to 24 hr. At 48 hr post‐infection, p16 expression continued to increase, but at this point, pRb expression started to decline significantly. Cell viability decreased in a dose‐dependent manner, down to 20% using 50 pfu/cell of adv. p16 . The addition of radiation therapy (RT) administered 24 hr post‐infection achieved only a slightly additive cytotoxicity. Adv. p16 therapy resulted in multiple mechanisms of cytotoxicity, including cell cycle arrest at the G0/G1 phase, induction of senescence, along with apoptosis. Ex vivo infection of C666‐1 cells with adv. p16 (25 pfu/cell) with subsequent implantation into scid mice completely prevented tumor formation, followed for up to 51 days. Our study demonstrates the potential efficacy of adv. p16 gene therapy for NPC, mediated through multimodal mechanisms of cytotoxicity. Future evaluations will examine strategies to increase in vivo tumor transduction with a view towards future clinical applications. © 2004 Wiley‐Liss, Inc.