| Summary: | 博士 === 國立陽明大學 === 生化暨分子生物研究所 === 100 === BO-1090, BO-1100, BO-1130 and BO-1131 are the derivatives of 3a-aza-cyclopenta[a]indene, a class of newly synthesized alkylating agents. In my present study, I demonstrated that novel derivatives may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on invivo xenografts. Among all, BO-1090 is the most potent and targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine-based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single-stranded breaks (Comet assay) and double-stranded breaks (γ-H2AX focus formation). Intravenous injection of BO-1090 significantly suppressed SAS or Cal27 subcutaneous xenografted and orthotopic implanted tumor growth in mice in comparison to control mice.
In preliminary drug combination studies when lung cancer cells were treated with BO-1509, a new modified derivative of BO-1012 (derivative of 3a-aza-cyclopenta[a]indene) lead to activation of survival and DNA repair protein that may cause resistance of BO-1509 in tumor cells. To overcome activation of survival and DNA repair protein, I combined BO-1509 with PI3 kinase inhibitor LY294002, which has property to suppress survival and repair pathway. Synergism was found between two drugs in several lung cancer cells including H460, CL-1-5, CL-25 and CL-83 in culture. In CL-1-5 and H460 xenografted mice, LY294002 in combination with BO-1509 significantly suppress the growth of tumor in comparison to the vehicle treated control mice and BO-1509 alone treated mice. Based on γH2AX foci formation assay, half of double strand break (DSB) in cell induced by BO-1509 was repaired by 72 h, while cells treated in combination of BO-1509 with PI3 kinase inhibitor still maintain DSB damage, this suggests the DNA repair inhibition by LY294002 in combination treatment. Initial finding also suggests that synergism between BO-1509 and LY294002 inhibitor may be due to inhibitory effect of LY294002 on Mre11 and Nbs1 proteins of MRN complex, which play important role in homologous DNA repair pathway.
In conclusion derivatives of 3a-aza-cyclopenta[a]indene have therapeutic potential either alone i.e. monotherapy of BO-1090 for oral cavity cancer treatment or in combination of BO-1509 with PI3 inhibitor in lung cancer.
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