COOPERATIVE INHIBITION OF RENAL-CANCER GROWTH BY ANTIEPIDERMAL GROWTH-FACTOR RECEPTOR ANTIBODY AND PROTEIN-KINASE-A ANTISENSE OLIGONUCLEOTIDE

Background: The expression of epidermal growth factor receptor (EGFR) and type I cyclic adenosine monophosphate (cAMP)-dependent protein kin ase (PKAI) is associated with neoplastic transformation. By use of hum an renal cancer cell lines (i,e,, 769-P, ACHN, A498, and SW839), we in vestigated the antiproliferative activity and the antitumor activity o f an anti-EGFR humanized chimeric mouse monoclonal antibody, MAb C225, and a novel mixed backbone 18-mer antisense oligonucleotide, HYB 190, that targets expression of the RI alpha regulatory subunit of PKAI, M ethods: The antiproliferative activity of MAb C225 and oligonucleotide HYB 190, alone or in combination, on different renal cancer cell line s was determined by monitoring cell growth in soft agar, In addition, the induction of apoptosis by treatment with the anti-EGFR antibody an d/or antisense PKAI oligonucleotides was evaluated by flow cytometric analysis of fragmented DNA, The antitumor activity of MAb C225 and oli gonucleotide HYB 190 was determined in athymic mice bearing establishe d ACHN tumor xenografts, Cell proliferation and tumor growth data were evaluated for statistical significance using Student's t test; report ed P values are two-sided. Results: MAb C225 and oligonucleotide HYB 1 90 inhibited colony formation in soft agar in a dose-dependent manner for all renal cancer cell lines tested, We observed a potentiation of growth inhibition and induction of apoptosis when 769-P cells and ACHN cells were treated with both agents. Combination treatment with MAb C 225 and oligonucleotide HYB 190 caused regression of ACHN tumor xenogr afts, whereas single-agent treatment only delayed tumor growth. Conclu sion: The combination of anti-EGFR MAb C225 and HYB 190 antisense PKAI oligonucleotides HYB 190 exhibited cooperative antiproliferative effe cts and cooperative antitumor effects on EGFR and PKAI-expressing huma n renal cancer cell Lines.