Antitumor activity of combined treatment of human cancer cells with ionizing radiation and anti-epidermal growth factor receptor monoclonal antibody C225 plus type I protein kinase A antisense oligonucleotide

Recent studies have suggested that selective inhibition of mitogenic pathwa ys may improve the antitumor activity of ionizing radiation, The epidermal growth factor receptor (EGFR) is overexpressed and is involved in autocrine growth control in the majority of human carcinomas. Protein kinase A type I(PKAI) plays a key role in neoplastic transformation and is overexpressed in cancer cells in which an EGFR autocrine pathway is activated, We used tw o specific inhibitors of EC;FR and PKAI that are under clinical evaluation in cancer patients: C225, an anti-EGFR chimeric human-mouse monoclonal anti body (MAb); and a mixed-backbone antisense oligonucleotide targeting the PK AI RI alpha subunit (PKAI AS). We tested in human colon cancer (GEO) and ov arian cancer (OVCAR3) cell lines the antiproliferative activity of MAb C225 and/or PKAI AS in combination with ionizing radiation. In vivo antitumor a ctivity was evaluated in nude mice bearing established GEO xenografts. Dose -dependent inhibition of soft agar growth was observed in both cancer cell lines with ionizing radiation, C225, or PKAI AS oligonucleotide. A cooperat ive antiproliferative effect was obtained when cancer cells were treated wi th ionizing radiation followed by MAb C225 or PKAI AS oligonucleotide. This effect was observed at all doses tested in both GEO and OVCAR-3 cancer cel l lines. A combination of the three treatments at the lowest doses produced an even greater effect than that observed when two modalities were combine d, Treatment of mice bearing established human GEO colon cancer henografts with radiotherapy (RT), MAb C225, or PKAI AS oligonucleotide produced dose- dependent tumor growth inhibition that was reversible upon treatment cessat ion. A potentiation of the antitumor activity was observed in all mice trea ted with RT in combination with MAb C225 or PKAI AS oligonucleotide, Long-t erm GEO tumor growth regression was obtained following treatment with ioniz ing radiation in combination with MAb C225 plus PKAI AS oligonucleotide, wh ich produced a significant improvement in survival compared with controls ( P < 0.001), the RT-treated group (P < 0.001), or the group treated with MAb C225 plus PKAI AS oligonucleotide (P < 0.001). All mice of the RT + MAb C2 25 + PKAI AS group were alive 26 weeks after tumor cell injection. Furtherm ore, 50% of mice in this group were alive and tumor-free after 35 weeks. Th is study provides a rationale for evaluating in cancer patients the combina tion of ionizing radiation and selective drugs that block EGFR and PKAI pat hways.