Abstract 5104: A novel N-mustard-quinoline conjugate is a potent agent against colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is the third leading cancer worldwide. The prognosis of patients diagnosed with CRC at the stage IV is poor with a 5-year survival rate less than 10%. Combination chemotherapy with platinum-based drugs and 5-fluorouracil (5-FU) remains the first line treatment, while the chemotherapy combined target therapeutic agents were decreasing the mortality of CRC patients. However, the efficacy of platinum-based drugs has often been limited because of the substantial risk for severe toxicities, including nephrotoxicity or neurotoxicity. Therefore, there is an unmet need to develop a novel drug for improving the treatment of advance colorectal cancer. We have previously designed and synthesized several series of DNA-directed alkylating agents with potent antitumor activity. Recently, one derivative of N-mustard-quinoline conjugates with hydrazinecarboxamide as a linker, designated as SL-1, was selected to explore its anti-colorectal cancer (CRC) activity because it was highly cytotoxic to a panel of CRC cell lines in culture. Flow cytometric analysis showed that treatment of CRC cells with SL-1 induced G2/M arrest and triggered apoptosis. We further demonstrated that SL-1 preferentially targeted on the selective guanine sequence by sequencing gel electrophoresis. By the aid of comet assay, SL-1 in combination with 5-FU resulted in increased DNA tail moments and induced more DNA damage. Evaluation of the potency of antitumor activity both in culture and in xenograft models, we observed that SL-1 was more potent than 5-FU and oxaliplatin against SW620, RKO and RKO-E6 (an oxaliplatin resistant-subline) cells. Notable, SL-1+5-FU were more efficacious than oxalipatin+5-FU in suppression the growth of RKO or SW620 in xenograft models. We further found that SL-1 enhanced 5-FU and induced more apoptosis by c-caspase 3 and TUNNEL staining. Additionally, histopathological examination showed that SL-1 by itself has no obvious kidney and liver toxicity in ICR mice comparing to cisplatin, oxaliplatin or 5-FU. Taken together, SL-1 alone or in combination with 5-FU may warrant our further development as a potential antitumor agent for the treatment of CRC patients. Citation Format: Tai-Lin Chen, Yan-Bo Chen, Chia-Ning Shen, Tsann-Long Su, Te-Chang Lee. A novel N-mustard-quinoline conjugate is a potent agent against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5104. doi:10.1158/1538-7445.AM2017-5104