Abstract 3512: Novel DNA alkylating agent BO-1090 is a potential candidate for oral cavity cancer therapy

Abstract

Abstract Human death from oral cancer is the 4th most common in male and over all 6th most common cause of cancer death in Taiwan. Surgery, radiotherapy in combination with chemotherapy is the most common line of treatment for oral cavity cancer. Although cisplain, 5FU, Docetexal, Pinyangmycin etc are the common drugs being used in clinic, there is no any specific drug for oral cavity cancer. In that direction BO-1090 a newly synthesized alkylating agent has potential to be more specific drug for oral cancer based on its potent in vitro cytotoxicty to oral cancer cells, such are OECM-1, SAS, OC3 and CAL-27 in comparison to other cancer cell lines, including lung cancer H1299, prostate cancer cell PC3 and neuronal cell line U87. BO-1090 target DNA for its cytotoxic effects that have been confirmed by alkaline gel shift assay, BrdU based DNA synthesis inhibition assay, Comet assay and γH2x detection. BO-1090 has been tested for its therapeutic potential in SAS cell xenograft mouse. At a dose of 60 mg/Kg i.v five times, it significantly delays the tumor growth in comparison to the control group of mice. Its tumor efficacy in SAS cell xenograft is better than the cisplatin at dose of 4 mg/kg i.v three times. Based on these preliminary results it suggests that B0-1090 can be a useful drug either alone or in combination with other knows drugs in oral cavity cancer therapy. As to the modes of actions of BO-1090, here is activation of CHK-2 check point in response to DNA damage by BO-1090 as well as late activation of p53 and p21. The late activation of P53 may be due to DNA replication blocked by BO1090. During propidium iodide staining based cell cycle analysis, BO-1090 induces G1/ S phase arrest in SAS cell that further confirmed by BrdU incorporation based pulse chase experiment. G1/S phase arrest may be due to combined effects of CDC 25A degradation and activation of p53 and p21 in response to BO-1090 induced DNA damage. G1/S phase arrest in cell by BO-1090 is not a common feature of a DNA alkylating agent, most of DNA alkylating agent induce G2/M phase arrest. In Annexin V based apoptosis assay, our results show that BO-1090 induces apoptosis in SAS and OECM-1 cell by time and dose dependent manner through caspase dependent pathway. By using bioinformatic approach and preliminary experiments suggest that PIM-1 may be also one of its molecular targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3512.