Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 280

system was used alone and in combination for clinical trials of prostrate cancer
[48] . Other suicidal gene systems like E. coli nitroreductase/5-[aziridin-1-yl]-2,
4-dinitrobenzamide)(NTR)/CB1954) and purine nucleoside phosphorylase/9-([ f ]-M-
2-deoxyerythropento-furanosyl) 6-methylpurine were used for prostrate cancer, using
adenovirus, and they show efficient killing of prostrate cancer cells in vitro [49] .
6.3.1.2 Tumor Suppression Gene Therapy
Mutations in p53 are widespread in human cancer and are observed in between 20%
and 75% of PCAs, more commonly in advanced metastatic tumors [50] . The gene
therapy based upon tumor suppressor genes ( p53 , retinoblastoma, and p21 ) has been
investigated in prostate cancer. Experimentally, the introduction of normal (wild-type)
p53 into prostate cancer in vitro and in vivo suppresses malignant phenotype, and
many clinical trials under progress are using these tumor suppressor genes [51,52] .
6.3.1.3 Induction of Apoptosis
Proapoptotic Bcl-2 family proteins, like bax , in elevated levels induce the secretion
of cytochrome c from mitochondria and activate cellular apoptotic machinery of cas-
pases (cysteine proteases) through intrinsic apoptotic pathway. Adenoviruses with the
bax -encoding gene have been effective in prostate tumor cell death by activating apop-
totic pathways in vitro conditions [53,54] . Adenovirus (Ad)-mediated overexpression
of genes for caspases ( caspases-1, caspases-2, and caspases-7 ) induces apoptosis
in the prostrate cancer cell line [55] . Polygene therapy of more than one proapop-
totic gene was found to be more effective in prostrate cancer [56] . The delivery of
genes producing ligands to death receptors (Fas and TRAIL) activates the apoptosis
in prostrate cancer cells [57,58] . A melanoma differentiation-associated gene-7 ( mda-
7/IL -24) was found to be active against prostate carcinoma, using adenovirus vector
in vitro and in vivo , by promoting mitochondrial dysfunction and inducing reactive
oxygen species [59] .
6.3.1.4 Immunomodulatory Gene Therapy
Modulation of the host's immune response to the cancer cells is one of the frequently
used strategies for cancer gene therapy. Further, the presence of a specific antigen on
prostrate cancer cells can facilitate tumor immunotherapy. The immunomodulation
gene therapy using both ex vivo and in vivo approaches has been utilized for preclini-
cal and clinical studies. One way to utilize gene therapy to optimize tumor antigen
presentation is through the targeted expression of cytokines in tumor cells. Various
cytokines, IL-2, IL-12, and granulocyte macrophage colony-stimulating factor (GM-
CSF), have been evaluated and have shown promising results in prostrate cancer
immunotherapy. These cytokines generally improve the activation of antigen process-
ing and presentation by macrophages and DCs [60] . Many clinical trials utilized GM-
CSF vaccines for the treatment of prostrate cancer [61-64] . Prostrate-specific antigens
have also been tried in clinical settings for prostrate cancer gene therapy [65,66] .