(The FASEB Journal. 2007;21:870.10)
© 2007 FASEB
Multigene Targeting with Antisense Oligodeoxynucleotides: An Exploratory Study Using Human Colorectal Cancer Cells
Mohamed-Salah I Abaza
Biological Sciences, Kuwait University, P. O. Box 5969, 13060 Safat, Kuwait
ABSTRACT
Aberrant expression of growth-promoting genes contributes to the growth advantage of tumor cells, targeting such genes with antisense ODNs might be useful in controlling the abnormal proliferation of cancer cells. However,targeting single genes or their products will be of limited utility for cancer therapeutics because only a partial suppression of cell proliferation was observed. Accordingly, complete suppression of tumor cell proliferation may require inhibition of multiple growth promoting genes. We examined the in vitro effects of liposmal antisense phosphorothioate oligodeoxynucleotides targeting c-myb, c-myc and cdc2 in the human colorectal cancer cell lines. mRNA and protein expression of c-myb, c-myc, and cdc2 were dramatically reduced after treatment with c-myb-, c-myc-, or cdc2-AS(S)ODNs. The combination antigene therapies targeting c-myb/c-myc (5–100%) and c-myc/cdc2 (5–95%) had much higher growth inhibitory effects than that of single antigen therapy (5–55%). The combination antigene therapy targeting c-myc/cdc2 also had greater growth inhibitory effects (10–100%) than that of single antigene therapy (5–60%). These combination therapies produced additive or synergistic effects in a dose and time dependent manner. The combination antigene therapy targeting c-myc/c-myc/cdc2 exhibited much higher growth inhibitory effects (10–90%) than that of single antigene therapy (20–50%). Flow cytometric analysis showed the growth arrest of cancer cells in S-phase after treatment with single or combination antigene therapies demonstrating that cancer cells are more susceptible to apoptosis. Our study suggests that the effectiveness of combination antigene therapy targeting c-myb, c-myc and cdc2 is much higher than that of individual antigene therapy. Combination antigene therapy is a promising approach for cancer therapy.
