Most anticancer agents have poor water-solubility and thus, have a higher risk of failure during the period of new drug discovery and development. Our previous exploration of water-soluble N-mustard-benzene conjugates has led to an anticancer drug candidate, Ureidomustin (1-[3-((2-(dimethylamino)ethyl) carbamoyl)phenyl]-3-[4- (bis(2-chloroethyl)amino)phenyl]urea hydrochloride. This agent exhibits a broad spectrum of antitumor activity. Ureidomustin shows potent therapeutic efficacy against various human solid tumor xenografts. Complete tumor remission was observed in nude mice bearing human breast carcinoma MX-1 xenograft treated with Ureidomustin. This was observed continuously for 75 days; no tumor relapse was detected and the average body-weight was recovered after ceasing of drug treatment. In addition, this water-soluble derivative exhibits potent antitumor activity against other tumor xenografts. This agent induced >95% suppression of human colon cancer HCT-116 and >99% suppression of prostate adenocarcinoma PC3 xenografts (subcutaneous implantation) in nude mice. We also found that this agent is as potent as Docetaxel (>93% suppression), but more potent than carboplatin (65% suppression) in nude mice bearing colon tumor 22Rv/HL2 (orthotropic implantation). Examination of the pathology changes of different organs removed from Ureidomustin treated mice showed that there are no apparently pathological changes between the control group and the drug treated groups. Moreover, the average body-weight of the drug treated mice recovered after stopping of drug treatment. These results indicate that Ureidomustin has very little toxicity to the host. Studies on the mechanism of action of this agent revealed that this compound is able to induce DNA interstrand cross-linking. Furthermore, the pharmacokinetic (PK) study revealed that Ureidomustin has an acceptable PK profile in rats with a half-life of 0.77 h. Rapid distribution and slow elimination were found after administrating this agent in rats. In summary, Ureidomustin is a promising candidate for clinical application and is currently undergoing further preclinical studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C166.