Adenovirus p16 gene therapy for prostate cancer

Abstract

Surgery, radiation, or hormone deprivation alone does not adequately affect local control of clinical or pathologic stage T3 prostate cancer. Lack of local cancer control ultimately leads to a higher incidence of morbidity, distant metastasis, and decreased survival, with patients having disease-specific mortality exceeding 75%. Other novel therapies against this devastating and common disease are needed for the achievement of long-term local cancer control. For this purpose, therapeutic interventions should target prostate-cancer cells at the molecular and cellular level in ways not possible by current modalities of cancer treatment. Any strategy that can modify the biologic behavior of these cells may potentially have the most significant clinical impact. As prostate cancer represents an accumulation of genetic mutations that causes a prostate cell to lose the ability to control its growth, one new approach against prostate cancer may be gene therapy. Identification of key missing or mutated tumor-suppressor genes that, when replaced, may inhibit or destroy prostate-cancer cells may have the best chance of clinical success. One such gene appears to be tumor-suppressor gene p16 (also known as MTS1, INK4A, and CDKN2). Tumor-suppressor gene p16 is an important negative cell-cycle regulator whose functional loss may significantly contribute to malignant transformation and progression. Alterations in the p16 gene and its protein expression often occur in prostate cancer. An adenoviral vector containing wild-type p16 (Adp16) had a high transduction efficiency in prostate-cancer cells both in vitro and in vivo. Moreover, prostate tumors injected with Adp16 expressed p16 and the adenoviral vector expressed the transgene for up to 14 days. Wild-type p16 inhibited prostate-cancer proliferation in vitro and markedly suppressed tumors in vivo. Pathologic evaluation of the Adp16-treated tumors showed dose-dependent necrosis and fibrosis. Although the mechanism of p16 inhibition in cancer remains to be elucidated, senescence and apoptosis may both be important; however, the data suggest that p16-induced growth inhibition can function independently of the retinoblastoma gene product.

Inhibition of Breast Tumor Cell Growth by Ectopic Expression of p16/INK4A Via Combined Effects of Cell Cycle Arrest, Senescence and Apoptotic Induction, and Angiogenesis Inhibition

“…Consistently, our previous studies have also indicated that adenoviral-mediated p16 gene transfer inhibited tumor growth of prostate cancer 24,42 and BCa 17, and suppressed angiogenesis 17 and metastasis 43 in BCa. While the majority of these studies correlated the p16's anti-proliferation effect to the anti-tumor ability, the exploration of other p16's functions related to this matter, especially the anti-angiogenesis property, is under-investigated.…”

Serum‐free suspension cultivation of PER.C6® cells and recombinant adenovirus production under different pH conditions

“…Among various viral vectors, adenovirus vectors have become one of most promising vehicles for gene delivery for therapeutic treatment and vaccination (Allay et al, 2000;Habib et al, 2001;Hsu et al, 1994;Mitani et al, 1994;Prevec et al, 1991;Rea et al, 1999). First-generation adenovirus vectors with the deletion of the essential viral E1 gene are replication defective in normal tissue cells and hence require complementing host cell lines with intrinsic E1 expression for production in vitro.…”

P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells

“…Inactivation of P16 is a frequent molecular event in most human cancers. Reactivation of P16 by transferring the P16 gene into cancer cells can induce G 1 arrest and cell apoptosis, suggesting that the P16 gene is a good target in cancer gene therapy 3. However, the molecular mechanism of P16-induced apoptosis in cancer cells is not clear yet.…”