Abstract
e14626 Ribonucleotide reductase (RR) is an essential enzyme that catalyzes the reduction of ribonucleotides to deoxyribonucleotides for use in DNA synthesis. Human RR consists of two subunits, a large subunit (R1) and small subunit (R2). RR provides an attractive target for anticancer therapy. In the present study, we synthesized phosphorothioated antisenses oligonucleotides (RR1AS1, RR1AS2, RR1AS3, RR1AS4 and RR1AS5) that target the R1 subunit of RR. We treated the human breast cancer cell line MCF-7 with antisenses, and doxorubicin or paclitaxel for 72 hours. Cell proliferation was measured by 3[H]- thymidine incorporation. The effects of the drug combinations were analyzed with Biosoft Calcusyn software. The levels of RR mRNA were measured by RT-PCR. We found two antisenses, RR1AS2 and RR1AS4, inhibited the proliferation of MCF-7 cells in a dose-dependent pattern (IC50s: 5.32+1.64μm and 2.57+2.72μm, respectively, 72 hours incubation). Also, RR1AS2 and RR1AS4 significantly suppressed the expression of RR1 mRNA. When MCF-7 cells were incubated in media with a mixture of antisense and doxorubicin or paclitaxel, both RR1AS2 and RR1AS4 synergistically increased the cytotoxicity of doxorubicin and paclitaxel. Calcusyn analysis showed that averaged combination index (CI) were 0.59+0.04, 0.66+0.22, 0.83+0.16 and 0.88+0.03, when MCF-7 cells were treated with the mixtures of RR1AS2 + doxorubicin, RR1AS2 + paclitaxel, RR1AS4 + doxorubicin and RR1AS4 + paclitaxel, respectively (CI<1 indicates synergism). These results suggest that the combination of RR antisenses and chemotherapeutic agents, such as doxorubicin or paclitaxel, may decrease both the dosages and side effects of both antisense oligonucleotides and chemotherapeutic agents (doxorubicin and paclitaxel) in cancer therapy. No significant financial relationships to disclose.
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