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  • During the past three decades platinum

    2021-02-23

    During the past three decades, platinum-based DNA-alkylating agents have been employed in the treatment of various cancers [14]. Oxaliplatin is currently used as a first-line treatment for colorectal cancer (CRC) [15]. Unfortunately, a large portion of CRC patients receiving oxaliplatin-based chemotherapy develop chemoresistance and metastatic cancer in a short period of time [16], [17]. In general, metastatic CRC (mCRC) patients were treated with the combination regimen FOLFOX, including oxaliplatin, 5-fluorouracil (5-FU), and leucovorin, which improved response rates to >50%; however, because of its undesirable grade 3 to 4 toxicity, this regimen has a highly negative impact on quality of life [18], [19]. Recently, standard chemotherapeutics have been used in combination with targeted therapeutic agents to ameliorate the mortality of patients with advanced CRC. However, the 5-year survival rate of patients with mCRC is still only 13% [19]. Therefore, the development of a novel treatment strategy for advanced CRC is required to fulfill this unmet need. Discovering a novel agent that maintains therapeutic efficacy and reduces undesirable side effects is a fundamental requisite. Notably, among a series of DNA-directed alkylating agents, SL-1 was the most cytotoxic to CRC GW311616 hydrochloride and showed limited toxicity to the animal [13]. Therefore, we sought to investigate the clinical potential of SL-1 as a therapeutic agent against CRC cells. However, the preferential sequence targeted by the quinoline moiety of SL-1 is unclear. In this study, we determined the sequence to which SL-1 preferentially binds, evaluated its anti-CRC activity, and determined its animal safety/toxicity. We also explored the efficacy and safety of the combination of SL-1 with 5-FU against CRC cells.
    Materials and Methods Chemicals and enzymes, chemical synthesis of SL-1, and cell culture are included in Supplementary Materials and Methods. The characteristics of the human CRC cell lines used in this study are summarized in Supplementary Table S1.
    Results
    Discussion While DNA-alkylating agents are used widely as first-line drugs for various cancers, the main limitations of simple alkylating agents are their lack of DNA sequence specificity [32]. Melphalan mainly induces dG-adducts at 5′-GNC-3′ and 5′-GC-3′ base pairs [32], whereas the platinum-based drugs principally bind to 5′-GG-3′ and 5′-GC-3′ base pairs [33]. In addition, the platinum-based alkylating agents generate more monoalkylation products than cross-links [33], [34], [35]. This observation may explain why platinum-based alkylating agents not only cause increased mutagenesis and carcinogenesis but also induce adverse side effects. To overcome these drawbacks, a DNA-directed alkylating agent with increased DNA-binding selectivity and reduced cytotoxicity was proposed [36]. In this study, we demonstrated that N-mustard-quinoline conjugates such as SL-1 and SL-2 preferentially targeted certain dG residues with the consensus sequence 5′-G-G/C-N-G-C/T-3′. This unique binding preference was not observed in the other N-mustard derivatives linked to different DNA-affinic carriers (such as acridine, 9-alinioacridines, or quinazolines) synthesized in our laboratory. As shown in Supplementary Figure S4 and S5, no distinct binding sequence was observed with an N-mustard 9-anilinoacridine conjugate (BO-1051) [6] and unmasked water soluble N-benzene mustard conjugates (BO-1055) [8]. These results suggested that the quinoline pharmacophore plays an important role in drug efficacy and safety. Intriguingly, McClean et al. [37] reported that when interacting with DNA, quaternary N-mustard 4-anilinoquinolinium conjugates (Supplementary Figure S7) bind strongly to AT-rich sequences in the minor groove. It remains unclear why the 6,7-methylenedioxy-quinoline pharmacophore in SL-1 prefers laying on 5′-G-C/T-3′, whereas the quaternary N-mustard 4-anilinoquinolinium conjugates favor binding to AT-rich minor grooves via their methyl quaternary salt. Since the linkers used in the SL-1 and the N-mustard-4-anilinoquinoline conjugate are hydrazinecarboxamide and aniline, respectively, we could not rule out the possibility that different linkers might induce varied sequence preferences before anchoring alkylation. However, unlike cisplatin and unmasked N-mustard conjugates, SL-1 creates sequence-dependent guanine adducts, which may reduce the inevitable side effects.