Antioncogenic Properties Of

The antitumor effects of AAV had been initially reported within a few years of identification of the virus itself when it was identified that infection of herpes simplex virus (HSV)-transformed hamster tumor cells with AAV delayed the appearance of palpable tumors and increased the survival time of the animals (70). Since then, several reports have confirmed the inhibition of viral oncogenesis by a variety of DNA viruses, including bovine papillomavirus-1 (71), human papillomavirus (HPV)-16 (72-74), and Epstein-Barr virus (75). Evidence from several reports also suggested that AAV infection might protect against human cervical cancer, in part, by interfering with HPV-induced tumori-genesis (76) although studies of Stickler et al. reported a lack of correlation of between AAV infection and cervical tumorigenesis in a Jamaican population (77).

Elucidation of the molecular mechanisms directing the antitumor properties of AAV identified a role for Rep78 in the inhibition of oncogenic transformation, specifically the downregulation of human c-fos and c-myc proto-oncogene promoters by Rep78 (78). Inhibition of HPV-16 P97 promoter activity (76) may partially account for the tumor inhibitory property of Rep78 in cervical cancer cells. A recent study reported that whereas Rep78 and Rep68 inhibited the growth of primary, immortalized, and transformed cells, Rep52 and Rep40 did not (79). Further Rep68 induced cell-cycle arrest in G1 and G2 with elevated cyclin dependent kinase inhibitor p21 and reduced cyclin E-, A- and B1-associated kinase activities. Rep78 was also found to arrest the cell cycle, preventing S-phase progression by binding to the hypophosphorylated retinoblastoma protein (79). The regulatory differences between Rep78 and Rep68 have now been mapped to the C-terminal zinc finger domain of Rep78. These studies indicate that Rep proteins exert heterologous control at both the molecular and cellular levels in inhibiting tumor growth. Despite the significance of Rep78 and Rep68 in tumor-suppression, potential utilization of Rep as a therapeutic molecule is limited by its toxicity (80). Thus, further advancements in highly tumor cell-specific delivery and/or expression of Rep gene is required before Rep can be used as a therapeutic molecule. Current advances in technology to identify both tissue-specific regulatory elements, and candidate ligands/molecules for receptors that are overexpressed in tumor cells should lead to the development of transductional and transcriptional targeting of rAAV vectors encoding Rep as a therapeutic molecule in future.

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