Biomedical Engineering Reference
In-Depth Information
5.2.6.3 Cancer Gene Therapy
Cancer is a disease of high incidence for which conventional treatments are not nec-
essarily effective for its complete cure. In prodrug therapy, also known as suicide
gene therapy, transgene products metabolize the nontoxic prodrug to a toxic drug,
resulting in cell death [61] . Combination of herpes simplex virus-TK/ganciclovir
(HSV-TK/GCV) or E. coli cytosine deaminase/5-fluorocytosine (CdA/5-FC) with
adenoviral vectors has also been used for suicide gene therapy; by delivering Ad
directly to the tumor, conversion of the prodrugs to the toxic form should occur only
within the site of the tumor, thereby creating a nontoxic form of chemotherapy. The
adenoviral vector-mediated suicide gene therapy approach has proven to be effective
in murine models of established tumors [62] .
Tissue or tumor-specific gene delivery is vital for achieving successful results in
suicide gene therapy. Adenoviral vector-mediated cytosine deaminase::uracil phos-
phoribosyltransferase (CD::UPRT) expression in the presence of 5-fluorocytosine
has shown high antitumor activity in human glioblastomas [63] . Adenoviral vectors
combine the Cre- lox P CD gene system with prostate-specific antigen (PSA) pro-
moter/enhancer to drive Cre recombinase activity that inhibits the growth of PSA-
producing prostate cancer cells in vivo [64] .
For the treatment of melanoma, the RGD (arginine-glycine-aspartic acid) fiber-
mutant adenoviral vector (Ad-RGD)-mediated HSVtk/GCV system is an attrac-
tive approach [65] , in which either melanoma-specific tyrosinase (Tyr) promoter or
tumor-specific telomerase reverse transcriptase (TERT) promoter instead of universal
cytomegalovirus (CMV) promoter is used in HSVtk/GCV treatment. This modifica-
tion exhibits high transgene expression specificity for melanoma cells. Recently, a
conditionally replicative Ad expressing UPRT has been constructed. UPRT can repli-
cate only in cancer cell-expressing transgene [66] .
The activation of cellular oncogenes and inactivation of tumor suppressor genes
occur by genetic alterations in tumors. Tumor suppressor genes, like Rb or p53 , can
mediate a dominant growth inhibitory function. These tumor suppressor genes repre-
sent interesting candidates for cancer gene therapy, the reason being that the expression
of these proteins would be expected to attenuate growth of tumor cells but not affect
normal tissues. Although it might be expected that long-term gene expression is crucial
for the success of tumor-suppressor therapy, transient expression of wild-type p53 in a
tumor cell will lead to apoptosis [66] . A number of clinical studies have evaluated the
use of Ad-p53 therapy in nonsmall cell lung cancer and squamous cell carcinoma of
the head and neck [67-69] . Clinically, the adenoviral vector was delivered either via
bronchoscope or percutaneously using a computed tomographic (CT) scan as a guide.
This treatment was generally well tolerated, even if many patients exhibited transient
fever. Cyclin inhibitors have also been used to suppress cell cycle progress in cancer
gene therapies employing Ads [70-72] . Proapoptotic proteins, such as bax, also pro-
mote cell death in tumors [68,69] . Another new approach to cancer gene therapy using
first-generation adenoviral vector is the development of oncolytic variants [73,74] .
The E1 gene products are most essential for binding the cellular tumor suppresor
genes p53 and Rb . These E1 gene products permit viral replication. Deletion of
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