Dual cancer-specific targeting strategy cures primary and d

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Dual cancer-specific targeting strategy cures primary
and distant breast carcinomas in nude mice.
Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14034-9
Authors: Sarkar D, Su ZZ, Vozhilla N, Park ES, Gupta P,
Fisher PB
Limitations of current viral-based gene therapies for
malignant tumors include lack of cancer-specific targeting and
insufficient tumor delivery. To ameliorate these problems and develop
a truly effective adenovirus gene-based therapy for cancer, we
constructed a conditionally replication competent adenovirus (CRCA)
manifesting the unique properties of tumor-specific virus replication
in combination with production of a cancer-selective cytotoxic
cytokine, melanoma differentiation associated gene-7/interleukin-24
(mda-7/IL-24), which embodies potent bystander antitumor activity.
Cancer cell selective tropism was ensured by engineering the
expression of the adenoviral E1A protein, necessary for viral
replication, under the control of a minimal promoter region of
progression elevated gene-3 (PEG-3), which functions selectively in
diverse cancer cells with minimal activity in normal cells. In the E3
region of this CRCA, we introduced the mda-7/IL-24 gene, thereby
mediating robust production of this cytokine as a function of
adenovirus replication. Infection of this CRCA (designated
Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and breast
cancer cells confirmed cancer cell selective adenoviral replication,
mda-7/IL-24 expression, growth inhibition, and apoptosis induction.
Injecting Ad.PEG-E1A-mda-7 into human breast cancer xenografts in
athymic nude mice completely eradicated not only the primary tumor
but also distant tumors (established on the opposite flank of the
animal) thereby implementing a cure. This dual cancer-specific
targeting strategy provides an effective approach for treating breast
and other human neoplasms with the potential for eradicating both
primary tumors and metastatic disease. Additionally, these studies
support the potential use of mda-7/IL-24 in the therapy of malignant
cancers.
PMID: 16172403 [PubMed - in process]

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