Inhibitory effects of the combination of HER-2 antisense oligonucleotide and chemotherapeutic agents used for the treatment of human breast cancer

Poor response to chemotherapy in patients with breast cancer is often assoc iated with overexpression of HER-2/neu. Interference with HER-2 mRNA transl ation by means of antisense oligonucleotides might improve the efficacy of chemotherapy. To test this hypothesis, eight breast cancer cell lines and a normal human fibroblast cell line were examined for their level of HER-2 e xpression, their sensitivity to phosphorothioate antisense oligonucleotides (AS HER-2 ODN), and to various chemotherapeutic agents, and the combinatio n of the two. No correlation was found between the intrinsic HER-2 level an d either the sensitivity to a particular chemotherapeutic agent alone, or t he amount of growth inhibition observed with a specific AS HER-2 ODN concen tration. Although sequence specificity and extent of AS HER-2 ODN inhibitio n of HER-2 synthesis were somewhat higher in the HER-2 overexpressing MDA-M B-453 and SK-BR-3 cells, we found that antisense treatment significantly se nsitized all of the breast cancer cells, even MDA-MB-231 and MDA-MB-435 cel ls, with approximately basal levels of HER-2, to various chemotherapeutic a gents. In addition, the combination of AS HER-2 ODN and taxol was shown to synergistically induce apoptosis in MDA-MB-435. These results demonstrate t hat overexpression of HER-2 would not be a prerequisite for the effective u se of AS HER-2 ODN as a combination treatment modality for breast cancer an d suggest that the use of AS HER-2 ODN, as part of a combination treatment modality, need not be limited to breast tumors that display elevated levels of HER-2.