Gene Delivery Using Viral Vectors - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 232

Up until now, AAV2-based vectors have been used to deliver different antiangio-
genesis genes to tumors in animal models, with positive results [135,136] . Recently,
Ponnazhagan used this approach and delivered both endostatin and angiostatin in a
single AAV2 shell [137,138] . The combination of endostatin and angiostatin has shown
synergistic protective efficacy on tumor development when AAV1/murine angiostatin
and AAV1/murine endostatin were injected intramuscularly into xenografted mice. The
combination of endostatin and angiostatin gene therapy suppressed LLC cells growth
more than either endostatin or angiostatin alone in the xenograft tumor mice, with
tumor growth inhibition of 91%, 62%, and 82%, respectively.
5.3.5.3 Immunomodulation
Immunomodulation by gene therapy for cancer has brought new hope to this field
by targeting both immune effector cells and tumor cells for gene transfer. Many
approaches have been exploited to use AAV vectors to deliver genes to enhance the
immune response against tumors through targeting either tumor cells or nontumor cells.
Recently, interferon (IFN) has an antitumor effect by directly inhibiting tumor cell pro-
liferation or immune modulation. Moreover, vaccination represents a very promising
alternative immunotherapy for cancer treatment. Transduction of B cells from chronic
lymphocytic leukemia (CLL) patients with AAV2/CD40 ligand led to the upregulation
of the costimulatory molecule CD80 on both infected and noninfected CLL cells, and
induced specific proliferation of HLA-matched allogeneic T cells (taken from different
individuals of the same species). Two or more individuals are said to be allogeneic to
one another when the genes at one or more loci are not identical, indicating the possi-
bility of vaccinating cancer patients, using tumor cells infected with AAV [139] .
5.3.5.4 Suicide Gene Therapy
The principle behind suicide gene therapy is the selective intratumoral activation of a
nontoxic drug by specific transfer of the activating transgene into tumor cells. AAV-
mediated delivery of the herpes simplex virus thymidine kinase ( HSV-TK ) gene using
albumin promoter and an  -fetoprotein enhancer can selectively kill  -fetoprotein-
positive hepatocellular carcinoma cells in a mouse model; this bystander effect was
demonstrated following the administration of ganciclovir (GCV) [62,80] .
5.3.5.5 Repair of Damaged Tumor Cells
Malignant tumor development is caused by imbalanced regulation of two groups
of genes: oncogenes and tumor suppressor genes. These tumor suppressor genes are
involved in cellular checkpoint control, preventing the passage of cells with damaged
DNA or other cellular damage through the cell cycle. Wild-type (wt) p53 cDNA trans-
fer into cancer cells can suppress the tumor phenotype in vitro and in vivo . rAAV/p53-
mediated transduction inhibited the growth of neoplastic cells with G1-S arrest and
also mediated cytotoxicity following apoptosis.
Zhang et al. studied the delivery of telomerase antisense RNA into MCF-7
cells using a hybrid adenovirus/AAV vector and demonstrated reduction in colony