Targeting Oncogenes to Improve Breast Cancer Chemotherapy

Abstract

Despite recent advances in treatment, breast cancer remains a serious health threat for women. Traditional chemotherapies are limited by a lack of specificity for tumor cells and the cell cycle dependence of many chemotherapeutic agents. Here we report a novel strategy to help overcome these limitations. Using triplex-forming oligonucleotides (TFOs) to direct DNA damage site-specifically to oncogenes overexpressed in human breast cancer cells, we show that the effectiveness of the anticancer nucleoside analogue gemcitabine can be improved significantly. TFOs targeted to the promoter region of c-myc directly inhibited gene expression by f40%. When used in combination, specific TFOs increased the incorporation of gemcitabine at the targeted site f4-fold, presumably due to induction of replication-independent DNA synthesis. Cells treated with TFOs and gemcitabine in combination showed a reduction in both cell survival and capacity for anchorage-independent growth (f19% of untreated cells). This combination affected the tumorigenic potential of these cancer cells to a significantly greater extent than either treatment alone. This novel strategy may be used to increase the range of effectiveness of antitumor nucleosides in any tumor which overexpresses a targetable oncogene. Multifaceted chemotherapeutic approaches such as this, coupled with triplex-directed gene targeting, may lead to more than incremental improvements in nonsurgical treatment of breast tumors. (Cancer Res 2006; 66(8): 4089-94)

DNA triple helices: Biological consequences and therapeutic potential

“…We have used TFOs targeted to the c-MYC gene to stimulate repair synthesis in the presence of an antitumor antimetabolite, gemcitabine, to increase its incorporation into DNA. We found that when used in combination, c-MYC-specific TFOs significantly increased the effectiveness of gemcitabine in inhibiting the growth of human breast tumor cells [33].…”

Commentary: Genetic modification through oligonucleotide-mediated mutagenesis. A GMO regulatory challenge?

“…It is referenced in the literature under other names such as targeted nucleotide exchange, chimeraplasty, oligonucleotidemediated gene editing, chimeric oligonucleotidedependent mismatch repair, oligonucleotide-mediated gene repair, triplex-forming oligonucleotides induced recombination, oligodeoxynucleotide-directed gene modification, therapeutic nucleic acid repair approach, targeted gene repair (see e.g. Andersen et al, 2002;Christensen et al, 2006;Cole-Strauss et al, 1999;de Semir and Aran, 2006;Igoucheva et al, 2006;Zhang et al, 1998).…”

“…Last but not least, the technique seems to offer opportunities for the future in the field of human gene therapy to correct point mutations, for instance in monogenic inherited diseases and cancer (Christensen et al, 2006;de Semir and Aran, 2006;Kmiec, 2003;Wu et al, 2001). The therapy using oligonucleotides or RNA/DNA chimeras can result in a fraction of cells in which the wild-type gene can be restored.…”

Platycodin D from Platycodonis Radix enhances the anti-proliferative effects of doxorubicin on breast cancer MCF-7 and MDA-MB-231 cells

“…The clinical therapeutic regimens for breast cancer include resection, chemotherapy, radiotherapy and biological therapy [2]. However, the treatments of breast cancer are commonly unsuccessful, because of its secondary recurrence, metastasis and drug resistance [3,4]. The chemotherapy drug doxorubicin (DOX), which is an anthracycline anti-cancer drug, has been widely used to treat breast cancer, leukemia and lung cancer by inhibiting DNA topoisomerase II and intercalating double strand DNA [5,6].…”