期刊
NEOPLASIA
卷 20, 期 2, 页码 119-130出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2017.11.006
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资金
- National Research Program for Biopharmaceuticals at the Ministry of Science and Technology of Taiwan [MOST 1052325-B-001-010]
- Ministry of Science and Technology, Taiwan [MOST103-2325-B-001-018, MOST104-2325-B-001-001, MOST 105-2325-B-001-001]
- Academia Sinica [AS-102-TPB13]
- Ministry of Science and Technology [MOST 105-0210-01-13-01]
- Academia Sinica
Efficacy and safety are fundamental prerequisites for anticancer drug development. In the present study, we explored the anti-colorectal cancer (CRC) activity of SL-1, a DNA-directed N-mustard-quinoline conjugate. The N-mustard moiety in SL-1 induced DNA strand breaks, interstrand cross-links (ICLs), G2/M arrest, and apoptosis, whereas its quinoline moiety preferentially directed SL-1 to target the selective guanine sequence 5'-G-G/C-N-G-C/T-3'. Notably, SL-1 was highly cytotoxic to various CRC cell lines. Experiments using xenograft models revealed that SL-1 was more potent than 5-fluorouracil (5-FU) and oxaliplatin for suppressing the growth of RKO and RKO-E6 (oxaliplatin-resistant subline) cells as well as metastatic SW620 cells. In addition, SL-1 combined with 5-FU was more effective than oxaliplatin and 5-FU for suppressing RKO or SW620 cell growth in mice. Significantly, compared with cisplatin, oxaliplatin, or 5-FU, SL-1 alone or in combination with 5-FU did not cause obvious kidney or liver toxicity in ICR mice. In summary, SL-(1), a DNA-directed alkylating agent, is established as an anti-CRC agent with high efficacy and low toxicity and thus warrants further development for the treatment of CRC patients.
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