Abstract
4050 Background: Bcl-2 confers resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We performed a preclinical evaluation of antisense (AS) Bcl-2 as an enhancer of the chemotherapeutic effect in the treatment of gastric carcinoma. Methods: AS Bcl-2 was used with 18-mer phosphorothiated oligonucleotides in the MKN-45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated by the MTT assay, and antitumor effect in vivo was evaluated by the nude mouse xenograft. Apoptosis was determined with TUNEL assay. AS Bcl-2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice in q2wks in vivo. Anticancer drugs were administered intraperitoneally four times in qwk. Results: Bcl-2 was downregulated to 60% of initial value after the treatment with 1.0 μM of AS Bcl-2 compared to the controls of random and mismatched ODNs. Drug sensitivity to doxorubicin (DOX), cisplatin (CDDP), and paclitaxel (TXL) was increased three- to four-fold when used in combination with AS Bcl-2, which was determined with IC50 values in comparison with the control. Increased drug sensitivity was associated with apoptosis, increasing in Bax, Poly (ADP-ribose) polymerase and decreasing in phosphorylated Akt. The antitumor effect of CDDP and TXL in vivo was significantly enhanced in combination with AS Bcl-2. Downregulation of Bcl-2 was observed at day 4 after the treatment with AS Bcl-2. AS Bcl-2 ODNs induced splenomegaly in association with increased serum IL-12, CD80 and CD83 expression, which was attenuated by methylation of the CpG motifs of AS Bcl-2, however, methylated CpG failed to negate the increased antitumor effect of AS Bcl-2. Conclusions: Combination treatment with AS Bcl-2 and anticancer drugs, including CDDP and TXL, may be a new strategy for enhancing the chemotherapeutic effect in the treatment of gastric carcinoma. No significant financial relationships to disclose.
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