Tumor Targeting 411 Transcriptional Targeting

Transcriptional targeting can be achieved by the use of an expression cassette which is activated by tissue specific promoters (TSPs) (167). The options are to use either a promoter with a high activity in tumor cells/tumor ECs or to use inducible promoters to achieve therapeutic transgene expression. Examples of promoters with high tumor-selective activity (minimal expression in normal cells) are, CXCR4, cyclooxygenase-2 (COX-2), survivin (a member of the inhibitor of apoptosis protein family) and pre-proendothelin-1 (PPE-1) a precursor protein for endothelin-1. The human CXCR4 gene is expressed at high levels in many types of cancers, but is repressed in the liver. Thus, the CXCR4 promoter has a "tumor-on" and "liver-off" status in vitro and in vivo, which make it a good candidate TSP for targeted cancer gene therapy approaches, (i.e., for melanoma and breast cancers) (168). COX-2, a key enzyme in the synthesis of prostaglandins and thromboxanes, is highly up-regulated in tumor cells, stromal cells and angiogenic ECs during tumor progression (60). COX-2 of EC promotes integrin aV^3-mediated EC adhesion, spreading, migration and angiogenesis (169). The COX-2 promoter has been used to direct expression of caspases to COX-2-overexpressing cancer cells, inducing apoptosis while normal cells showed no caspase activation (170). Similarly, systemic application of an adenovirus containing a reporter gene expressed from the survivin promoter resulted in high levels of reporter gene expression in tumor cells only (171). PPE-1 is the precursor protein for endothelin-1 (a potent vasoconstrictor and smooth muscle cell mitogen) and is synthesized by ECs. The murine PPE-1 promoter contains a hypoxia-responsive element that increases the promoter activity in hypoxic tissue, like in marginally vascularized tumors (172,173). Greenberger et al. used a chimeric death receptor transgene, coding for Fas and TNF receptor 1 under the control of the PPE-1 promoter, to sensitize cancer cells to the proapoptotic effect of TNF-a and to induce specific apoptosis of ECs in vitro (174).

Table 2

Tumor Targeted Antiangiogenic Gene Therapy

Table 2

Tumor Targeted Antiangiogenic Gene Therapy

Vector

Targeting motif

Target

Ref.

Polycation

COX-2 promoter

Tumor cells

(170)

polyethylenimine

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