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Adenovirus-Mediated Retinoblastoma 94 Gene Transfer Induces Human Pancreatic Tumor Regression in a Mouse Xenograft Model

¹ Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain;² Genes and Disease Program, Center for Genomic Regulation, Barcelona, Spain; and³ Titan Pharmaceuticals, Inc., San Francisco, California

Purpose: Gene transfer of a truncated variant of the retinoblastoma (RB) gene encoding a M_r 94,000 protein that lacks the NH₂-terminal 112 amino acid residues, termed RB94, has been shown to inhibit proliferation of several human tumor cell types. We have assessed its therapeutic effectiveness on pancreatic cancer, one of the most aggressive and therapy-resistant types of cancer. For this purpose, preclinical studies aimed to evaluate the therapeutic potential of RB94 gene transfer in pancreatic cancer were carried out.

Experimental Design: We have compared the antiproliferative effects of adenovirus-mediated gene transfer of RBwt and RB94 at the in vitro and in vivo levels in three RB-positive human pancreatic tumor cell lines: (a) NP-9; (b) NP-18; and (c) NP-31. We have also examined their effects on cell cycle and their capacity to induce apoptosis.

Results: In vitro results indicate that RB94 gene transfer has stronger antiproliferative effects compared with RBwt. RB94 transduction correlated with accumulation at the S-G₂ phase of the cell cycle in the three cell lines tested and induction of apoptosis in two of them. In vivo studies show significant decreases in the growth rate of tumors treated with Ad-RB94 when compared with those treated with Ad-RBwt. Moreover, terminal deoxynucleotidyl transferase-mediated nick end labeling analyses of Ad-RB94-treated tumor sections revealed that only RB94 is able to significantly induce apoptosis.

Conclusions: RB94 gene expression has antiproliferative effects also in human pancreatic tumor cells, being more effective than wild-type RB in preventing tumor growth.

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