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Cooperative Inhibitory Effect of Novel Mixed Backbone Oligonucleotide Targeting Protein Kinase A in Combination with Docetaxel and Anti-Epidermal Growth Factor-Receptor Antibody on Human Breast Cancer Cell Growth¹

Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università Federico II, 80131 Napoli, Italy [G. T., R. C., G. P., S. P., A. R. B., F. C.]; Hybridon Inc., Cambridge, Massachusetts 02139 [S. A.]; and University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [J. M.]

Type I protein kinase A (PKAI) is overexpressed in the majority of human tumors and plays a relevant role in neoplastic transformation, conveying mitogenic signals of different growth factors and oncogenes. Inhibition of PKAI by antisense oligonucleotides targeting its RI regulatory subunit results in cancer cell growth inhibition in vitro and in vivo. We have recently shown that a mixed backbone oligonucleotide targeting RI can cooperatively inhibit human cancer cell growth when combined with selected cytotoxic drugs. In the present study, we have used HYB 165, a novel DNA/RNA hybrid mixed backbone oligonucleotide that exhibits improved pharmacokinetic and bioavailability properties in vivo and is presently undergoing Phase I trials. We have shown that HYB 165 exhibits a dose-dependent inhibitory effect on ZR-75-1 cells and a cooperative activity with docetaxel, a cytotoxic drug active in breast cancer. The antiproliferative activity is accompanied by increased apoptosis, as compared with each single agent. On the basis of our previous demonstration of a structural and functional relation between PKAI and epidermal growth factor receptor, we have performed a double blockade of these pathways using HYB 165 in combination with monoclonal antibody (MAb) C225, an anti-epidermal growth factor receptor chimeric MAb. The two compounds determined a cooperative growth inhibitory effect on ZR-75-1 cells and increased apoptosis. To study whether different biological agents and cytotoxic drugs can interact together, low doses of HYB 165, MAb C225, and docetaxel were combined causing an even greater cooperative effect toward growth inhibition. Finally, we have demonstrated that each single agent is able to induce bcl-2 phosphorylation and that the three agents, used in combination at suboptimal doses, determine a greater degree of bcl-2 phosphorylation and cause apoptosis of the majority of ZR-75-1 cells. These findings provide the basis for a novel strategy of treatment of breast cancer patients because both HYB 165 and MAb C225 are presently under clinical evaluation.

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