A Novel Hybrid Bifunctional Alkylating Agent That Potently Suppresses the Growth of mCRC Cells Xenografts and Patient-Derived Organoids

Background: Hitherto metastatic colorectal cancer (mCRC) is the basis for second-leading death of all cancers. As first-line chemotherapy in mCRC treatment, an antiangiogenic combination bevacizumab with FOLFOX4 improved competence and overall survival (OS). We developed a new hybrid small molecule dual properties as therapy to study its synergistic effect on CRC cell lines patient-derived organoids. Materials methods: The anti-proliferative was analyzed by PrestoBlue assay using organoids (PDO). Antiangiogenic property has been assessed docking model, molecular, vitro, vivo methods. Xenografts PDOs were tested BO-2762 efficacy 20 mg/kg (i.v) nude mice. For safety profiling toxicology, ICR mice model used various pathological analyses. Results: identified ant proliferative IC50 ranged between 0.5 4.5 μM against PDO lines. Subsequently, DNA damage observed inter-strand cross-linking (ICL) alkaline agarose gel ICL affects cellular synthesis arresting cycle at S Phase upon apoptosis. Angiogenesis inhibition occurred inhibiting VEGFR2 activation endothelial cells 3 mouse well. Based vitro analysis, non-metastatic (LoVo, SW620, LS1034, HT-29) (T53 T112) induced xenografts have shown effective growth 85.8%, 83.0%, 75.4%, 44.8% respectively. tremendous more than 90% reduction. Pathological analysis elaborates treatment elevating γ-H2AX CD31 expression treated tumor tissues. Biosafety promising parameters blood chemistry pathology analysis. Conclusions: potent anti-cancer agent mCRC. indicates that driven bifunctional serious inhibited angiogenesis leading satisfying profile. No conflict interest.