Mutant Adenoviruses Selectively Replication-Competent in Tumor Cells
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MUTANT ADENOVIRUSES SELECTIVELY REPLICATION-COMPETENT IN TUMOR CELLS Makoto Sunamura* First Department of Surgery Tohoku University School of Medicine Sendai Japan
INTRODUCTION The development of a malignant tumor is a multi-step process resulting from the mutation of several specific genes involved in the control of cell growth and programmed cell death. Most retroviral and adenoviral vectors containing a deletion in an essential gene required for viral propagation are unable to replicate in cells. Rather than destroying tumor cells through viral replication, these vectors rely on the delivery of therapeutic genes to destroy tumor cells. One of the major difficulties with this approach is the daunting goal of delivering genes to every cancer cell of a tumor. The idea of using viruses as antitumor agents has been emerged from different groups. The adenovirus relies on cellular replication factors for efficient viral DNA replication. Thus, the virus must induce cell cycle progression for productive infection in normal growth-arrested cells. Adenovirus E1 gene products, in addition to transactivating the other early gene promoters, prepare the cellular environment for optimal viral replication by associating with a number of key cell cycle proteins. Selectivelyreplicating viruses may overcome the limitation of gene transfer of adenoviral vectors. Virus replication in a small fraction of the tumor cells leads to amplification and extension of the antitumor effect. Cell killing is due to viral replication and cell lysis exclusively.
Phone: +81-22-717-7205, Fax: +81-22-717-7209, E-mail: msun-thk#umin.u-tokyo.ac.jp
Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic /Plenum Publishers, New York, 2000.
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E1B MUTATED ADENOVIRUS The p53 gene is mutated in more than half of human tumors (Greenblatt et al., 1994) indicating that it plays a key role as tumor suppressor. In support of this notion, is the evidence that members of the cancer-prone Li-Fraumeni families carry germline p53 mutations (Malkinet et al., 1990) and p53 null mice frequently develop tumors (Donehower et al., 1992). On the other hand, reconstitution of the wild-type p53 gene expression suppresses the growth of different human and mouse tumor cells in culture through the induction of cell-cycle arrest and/or apoptosis (Baker et al., 1990; Yonish-Rouach et al., 1991).
p53, tumor suppressor protein, mediates cell cycle arrest and/or apoptosis in response to DNA damage caused by chemotherapy, radiation or foreign DNA synthesis during viral replication. The p53 protein is normally present in minute levels and is probably inactive. However, when cells are exposed to DNA damage or start to divide aberrantly, p53 levels rise and the protein production is switched on. Activated p53 gene acts to block cell division and induce programmed cell death of the damaged cell. As p53 is functionally inactivated in many human tumors, one strategy to impede their growth is through transduction of wild-type p53 g
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