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  • We have compared the potency of a series of DNA

    2019-07-09

    We have compared the potency of a series of DNA-directed alkylating agents, including N-mustard-acridine, N-mustard-quinoline, and N-mustard-quinazoline conjugates previously synthesized in our laboratory [7], [13], and currently used drugs (oxaliplatin, cisplatin, or 5-FU) for the treatment of CRC patients. Among these compounds, we found that SL-1 was the most effective. Notably, we found that p53-dependent RKO EGTA and metastatic p53-MT SW620 cell lines were sensitive to SL-1, indicating that SL-1 may serve as a useful agent against p53-MT CRC cells. Additionally, SL-1 also effectively killed p53-independent RKO-E6 cells, which were resistant to cisplatin. In addition, SL-1 was more potent than cisplatin in causing DNA strand breaks and ICLs and in triggering apoptotic cell death. For the drug safety study, we found that SL-1 displayed low toxicity to normal colon epithelial FHC cells, indicating that SL-1 has a wider therapeutic window than the therapeutic agents used clinically (e.g., oxaliplatin, cisplatin, 5-FU, and irinotecan). These results strongly suggest that SL-1 targets to a wide spectrum of CRC cell lines, including mCRC cells. We demonstrated that SL-1 alone exhibited more tumor suppression in nude mice bearing RKO (p53-dependent) or RKO-E6 (p53-independent) xenografts than 5-FU, cisplatin, or oxaliplatin. This result suggests that SL-1 may act as an agent against CRC cells that are resistant to oxaliplatin. Although FOLFOX resulted in significantly increased response rates and improved survival, the combination treatment with oxaliplatin and 5-FU still manifested an increase in the side effects of these two drugs, such as bone marrow suppression, gastrointestinal toxicity, delayed neurotoxicity, and, less frequently, congestive heart failure [38]. Therefore, a new strategy for the treatment of CRC patients with combination therapy that would minimize the unpleasant side effects is urgently needed. In the present study, we showed that 5-FU synergistically increased the cytotoxicity of SL-1 against various p53-WT and p53-MT CRC cell lines in vitro. Furthermore, the combination of SL-1+5-FU synergistically triggered apoptotic cell death and increased the tail moment by damaging DNA. In addition, we found that the antitumor effects of the combination of 5-FU and SL-1 were more potent than those of oxaliplatin+5-FU in mice bearing RKO (p53-WT) and metastatic SW620 (p53-MT) xenografts. Accordingly, the combination of SL-1+5-FU is a potential regimen for the treatment of patients with CRC. Most alkylating agents have good therapeutic efficacy in cancer cells but are toxic to normal cells. Based on the design principles of DNA-directed alkylating agents, SL-1 might alleviate side effects in comparison to other alkylating agents because the DNA sequence preference of SL-1 may reduce its toxicity to animals. We evaluated the toxicity of SL-1 by intravenously injecting the compound into ICR mice. We did not observe obvious damage to the major organs or blood biochemistry changes in the SL-1–treated mice. Conversely, we observed that 5-FU, cisplatin, and oxaliplatin induced some toxicity, such as cytopenia, nephrotoxicity, and liver toxicity, respectively. We also confirmed the kidney damage caused by cisplatin and the spectrum of changes in focal vascular injury and cellular swelling. Moreover, cisplatin treatment increased the BUN value by 30% after 2 days. Additionally, the platelet and neutrophil counts were decreased by oxaliplatin, as reported previously [29], [31]. These results indicated that SL-1 at the tested dose has a better safety profile in animals than the other tested control compounds. SL-1 was the first designed DNA-directed alkylating agent shown to be less EGTA toxic in vivo. However, whether the selective alkylation by SL-1 is a reason for reduced adverse side effects warrants further investigation. In summary, the quinoline moiety in SL-1, which functions as a DNA-affinic carrier, may play a key role in defining the DNA-binding geometry and maintaining the potential region and sequence specificity of the alkylation. SL-1 alone or in combination with 5-FU displayed potent antitumor efficacy in nude mice bearing RKO (p53-WT) and metastatic SW620 (p53-MT) xenografts, suggesting that this agent may be effective for the treatment of patients with mCRC. Remarkably, compared with other antitumor agents, SL-1 and SL-1+5-FU displayed a better safety profile. Accordingly, SL-1 has great potential for development as an anticancer agent for the treatment of CRC patients.