Abstract
DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3μM) and very weak activity in osteosarcoma (IC50 >10μM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent.
Highlights
Alkylating agents are a part of the standard of care regimens for a number of pediatric and adult malignancies
BO-1055 inhibits proliferation and induces cell death in different sarcoma cell lines and cultures derived from patient samples with minimal toxicity to benign cells
A representative sample of growth inhibition curves for sarcoma cell lines are shown in Figure 1C with mean IC50 for BO-1055
Summary
Alkylating agents are a part of the standard of care regimens for a number of pediatric and adult malignancies. Used alkylating drugs play a significant role in the management of soft tissue sarcomas and Ewing sarcoma, both as first-line and second-line treatments [1, 2] albeit with substantial toxicities. We linked a benzene moiety with various hydrophilic side chains to the N-mustard moiety and evaluated the cytotoxicity in various cancer cell lines in vitro and in human xenograft models [6]. Of these agents, BO-1055 (water-soluble Ureidomustine) was found to have a broad spectrum of antitumor activity with a favorable safety profile and pharmacokinetics in pre-clinical studies [7, 8]. We evaluated its efficacy in sarcomas and performed a comprehensive toxicity screening in a range of benign cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
