Abstract B253: Novel water-soluble phenyl N-mustard-benzenealkylamide conjugate, BO-2094, potent agent for treatment of human colorectal cancer.
Authors: Tsai Tung-Hu , Tala Satishkumar D. , Ou Tai-Hsin , Lin Yi-Wen , Tala Kiranben S. , Wu Ming-Hsi , Lee Te-Chang , Su Tsann-Long 
Published: August 2014

Colorectal cancer (CRC) is the second leading cause of cancer related death in the United States and Europe. Surgery, radiotherapy, and chemotherapy are the main strategies for cure of CRC patient. However, the mortality risk associated with CRC is metastasis, which may be diminished by systemic treatments. Therefore, there is an urgent need of finding a better agent to treat CRC. Recently, we have synthesized a series of novel water soluble and chemically stable phenyl N-mustard- benzenealkylamide conjugates, which is consisted of phenyl N-mustard pharmacophore and benzenealkylamide moiety bearing a variety of hydrophilic alkylamide side chains. Of these conjugates, BO-2094 exhibits a broad spectrum of antitumor activity against a panel of human leukemia and solid tumor cell lines in vitro and potent therapeutic efficacy in various tumor xenograft-moles. This agent is able to induce DNA interstrand cross-linking, cell cycle arrest at sub-G1 and G2/M phase, and cell death via apoptosis. Particularly, BO-2094 displays potent antitumor activity in nude mice bearing human colon cancer HCT-116 and H334 xenografts. More than 95% tumor suppression was observes when BO-2094 [30 mg/kg, once per day for 6 consecutive days (QD×6), via intravenous injection (iv. inj.)] was used alone. The combination of BO-2094 and 5-FU at ratios of 1:3 induced synergistic cytotoxicity to HCT-116 cells in vitro. Notable, the growth of HCT-116 xenografts in nude mice was almost completely suppressed (&gt;98% suppression) when co-treated compound BO-2094 (30 mg/kg, QD×6, iv. inj.) with 5-FU [75 mg/kg, every 7 days for 2 doses (Q7D×2), intraperitoneal injection (ip. inj.)]; all mice (n=5) survived on day 35. The results revealed that the combination of BO-2094+5-FU is superior to that of oxaliplatin [15 mg/kg every 3 days for 3 doses (Q3D×3), iv. inj.] and 5-FU [75 mg/kg, Q7D×2, ip. inj.]. It should be noted that 2 of 5 mice died on day 28 when mice were co-treated with oxaliplatin+5-FU, indicating that the combination of BO-2094+5-FU is less toxic to the host. The early preclinical studies of BO-2094 showed that this agent is likely to have no cardiac arrhythmic side effect based on hERG assay and has low toxicity to the drug treated mice based on a 14-day acute iv injection study. The present studies indicate that the combination of compound BO-2094+5-FU has great potential benefit for the treatment of advanced colon cancer.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B253.

Citation Format: Tung-Hu Tsai, Satishkumar D. Tala, Tai-Hsin Ou, Yi-Wen Lin, Kiranben S. Tala, Ming-Hsi Wu, Te-Chang Lee, Tsann-Long Su. Novel water-soluble phenyl N-mustard-benzenealkylamide conjugate, BO-2094, potent agent for treatment of human colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B253.