Adenoviral mediated transduction of adenoid cystic carcinoma by human TRAIL gene driven with hTERT tumor specific promoter induces apoptosis

Abstract

Adenoid cystic carcinoma (ACC) is a common malignant tumor in salivary glands.

Unfortunately, current treatment modalities which include surgery, radiation and

chemotherapy have limited success rates. To develop new treatment strategies we

hypothesized that a cancer-specific apoptotic ligand driven by a tumor specific promoter

would specifically induce apoptosis in ACC. To test this concept, we selected tumor

necrosis factor-related apoptosis-inducing ligand (TRAIL) and the human telomerase

reverse transcriptase (hTERT) promoter. The latter is highly active in 85% of human

cancer cells while it is mostly inactive in somatic cells. Using immunohistochemistry we

confirmed that ACC samples but not normal salivary cells were positive for hTERT.

Similar results were also seen in an ACC cell line, SACC-83. We then constructed first

generation Ad5 vectors which used the hTERT promoter to drive TRAIL (AdTERT-

TRAIL). Transduction of SACC-83, but not of control human embryo-fibrocyte lung

(HEL) cells, led to apoptosis as measured by MTT assay and flow cytomerty. We used

the SACC-83 cells for a subcutaneous tumor model in vivo. Intratumoral injections of

AdTERT-TRAIL (5x109 particles/ tumor) but not of AdTERT-EGFP or PBS resulted in

significant (p