Abstract 2453: The role of p21 in the toxicity of mitomycin C and decarbamoylmitomycin C

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Abstract The mitomycins are a family of antitumor antibiotics made by Streptomyces. One member of this family, mitomycin C (MC), is currently used to treat certain cancers. Its mode of action has been extensively examined. In comparison, 10-decarbamoyl mitomycin C (DMC) has not been the object of such intense investigation. It has recently been found to form similar or identical adducts with DNA as mitomycin C (MC). In particular, DMC generates a unique stereoisomeric interstrand crosslink (beta isomer, β-ICL). Although the DNA-adducts of both drugs share common structural features, the biochemical responses to the two drugs are different. In particular, contrary to MC, the DNA-adducts generated by DMC treatment (β-ICL) rapidly activate a p53-independent signal transduction pathway. Thus, the study MC-DMC provides an ideal model for identifying structural features determining the cell signaling outcome in the presence or the absence of a functioning p53 pathway. In particular, we are interested in correlating MC and DMC-adducts structures with the role of p21 in the toxicity of the α-ICL and β-ICL. In this report, we present the following preliminary results 1) Synthesis of the beta DNA monoadduct of DMC via post-oligomerization methods 2) Role of p21 in the upstream p53-independent signaling pathway in response to MC/DMC and the α-ICL. Citation Format: Elise Champeil, Shu-Yuan Cheng, Bik Tzu Huang, Jiwon Seo. The role of p21 in the toxicity of mitomycin C and decarbamoylmitomycin C. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2453. doi:10.1158/1538-7445.AM2015-2453

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