Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system

Abstract

Introduction In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), α-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin.

Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma

“…Enhanced specificity was achieved by placing the CRAd E1A gene under the transcriptional control of the tumor selective promoter CXCR4. In this regard, the CXCR4 gene promoter revealed a superior ''breast cancer-on/liver-off'' profile in a preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system [18]. Furthermore, recent evidence points to the SDF-1a-CXCR4 complex as having an important role in progression to metastasis in several tumor contexts [13,24].…”

Organ selectivity in metastasis: regulation by chemokines and their receptors

“…It was observed that a relatively high transcriptional activity of the CXCR4 promoter exists in breast tumor cells [93,94]. Recent studies also indicate that elements which play key roles in breast malignancy regulate CXCR4 expression.…”

Cytotoxic Gene Therapy for Human Breast Cancer In Vitro

“…Despite initial enthusiasm for this form of treatment, clinical trials have been disappointing [2]. Vector targeting and TSPs are being investigated to overcome nontumor cell toxicity and poor transfection efficiency that limit the effectiveness of suicide gene therapy [6].…”

“…However, cytotoxicity has resulted from activation of HSV-TK in non-tumor cells [3][4][5]. Tumor-specific promoters (TSP) are being investigated as a strategy to improve transcriptional specificity [6].…”