Applications of Gene Therapy - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 281

6.3.1.5 Suppression of Oncogenes with Antisense
Oligonucleotides
Antisense molecules are synthetic oligodeoxynucleotides (ODN) that are designed
such that they can hybridize specifically to the coding mRNA inside the cell. Once
inside the cells, they pair with the targeted mRNA and obstruct its protein transcrip-
tion. Antisense ODNs have been used in prostrate cancer against a variety of ono-
genes like c-myc [67] and bcl-2 [68] .
6.3.1.6 Oncolytic Viruses
Viral vectors may themselves be designed to target and kill tumor cells without inser-
tion of a foreign transgene. These viruses generally replicate within the cancer cells,
causing cellular death. For prostrate cancer, many oncolytic virus were utilized in
experimental models and in clinical settings, such as adenovirus (CN-706, ONYX-
015) and herpes simplex virus (G-207) [69-71] .
6.3.2 Breast Cancer
Breast cancer poses a major health problem worldwide. In the United States, there
were an estimated 194,280 new cases in 2009, and 40,610 cases were expected to die
in that year [39] . The cure rate of advanced or recurring breast cancer is below 5%, so
the usual goal of treatment is prolongation of survival or improvement of quality of
life, not cure. Conventional therapy for breast cancer includes surgery, chemotherapy,
radiation therapy, and hormonal therapy. Although these treatment strategies provide
acceptable response rates and improve overall survival in patients with breast cancer,
they are generally not selective and induce cytotoxicity in normal as well as cancer
cells. Hence, novel treatment strategies are required for patients with metastatic dis-
ease or cancers unresponsive to standard radiation, hormone, and chemotherapy. The
various gene therapy strategies that have been used for experimental models and in
clinical trials are discussed below.
6.3.2.1 Suicide Gene Therapy
As for other types of cancer, suicide gene therapy has also been investigated for breast
cancer. Many preclinical results have demonstrated significant antitumor effects of sui-
cide genes (HSV- tk , CD, and cytochrome P450 ), hence these are now undergoing phase
I/II clinical trials in patients with different kinds of cancer, including breast cancer. In
a phase I trial for breast cancer, direct injection of CD plasmid was given into meta-
static skin lesions of 12 breast cancer patients. The expression of CD occurred in almost
all the patients. When prodrug (fluorocytosine) was given to the patients, two patients
showed tumor regression. However, two other patients showed tumor regression without
prodrug treatment [72] . In another clinical study, retrovirus was used to deliver the P450
2B6 gene (MetXia-P450) in nine breast cancer and three melanoma patients. Upon oral
administration of cyclophosphamide, the patients had a stable diseased condition [73] .