Abstract 823: Water-soluble ureidomustine (BO-1055) potently suppresses orthotopic 22Rv/HL2 prostate tumor xenografts: early preclinical studies

Abstract

Abstract In developed countries, prostate cancer (PCa) is one of the leading causes of death in men. PCa often recurs and metastasizes after an initial response to hormone therapy. Once PCa progresses to the castration-resistant stage, it becomes incurable. New and effective agents against PCa are therefore urgently needed. The objective of this study is to evaluate the antitumor activity of ureidomustine (BO-1055), which is a chemically stable and water-soluble phenyl N-mustard-benzamide conjugate previously synthesized from our laboratory. We previously demonstrated that ureidomustine exhibited potent therapeutic efficacy in nude mice bearing various human tumor xenografts, such as human colon cancer HCT-116 and prostate adenocarcinoma PC-3 xenografts (subcutaneous implantation), inhibiting growth by >95% and >99%, respectively. To broaden the antitumor spectrum of this agent, we evaluated the therapeutic efficacy of ureidomustine in nude mice bearing 22Rv/HL2 human PCa tumors implanted at an orthotopic site. The results showed that ureidomustine was as efficacious as docetaxel (>92% tumor suppression) and more potent than carboplatin (62% suppression) against 22Rv/HL2 PCa tumors in an orthotopic xenograft model. It revealed that ureidomustine exhibited low toxicity in mice, with no apparent pathological changes. We also studied the cytotoxicity of ureidomustine against normal murine cells and human hematopoietic stem cells (cord blood CD34+). The results showed that this agent exhibited low cytotoxicity against human hematopoietic stem cells (cord blood CD34+), primary human endothelial cells, and mesenchymal stem cells (BSC). Moreover, we performed the early preclinical studies including pharmacokinetics in rats, rat plasma protein binding, metabolic stability in rat liver microsomes, the 14 day intravenous acute toxicity in mice, and the biodistribution in rat, to determine whether this agent is a candidate for future clinical studies. The results indicate that ureidomustine is as potent as docetaxel against 22Rv/HL2 PCa cells in orthotopic xenograft models with low toxicity. In addition, this agent has low toxicity to human hematopoietic stem/progenitor cells and stromal cells such as BM-derived endothelial cells (BMEC) and MSC. Furthermore, early preclinical studies (ADME) suggest that ureidomustine has high potential for the treatment of advanced PCa in the clinic. Citation Format: Tsann-Long Su, Yi-Ren Chen, Jae-Hung Shieh, Tung-Hu Tsai, Malcolm A.S. Moore, Te-Chang Lee. Water-soluble ureidomustine (BO-1055) potently suppresses orthotopic 22Rv/HL2 prostate tumor xenografts: early preclinical studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 823. doi:10.1158/1538-7445.AM2014-823