Preclinical Evaluation of Anticancer Efficacy and Pharmacological Properties of FBA-TPQ, a Novel Synthetic Makaluvamine Analog
2012
Sadanandan E. Velu | Ming-Hai Wang | Ruiwen Zhang | Wei Wang | Dwayaja H. Nadkarni | Sukesh Voruganti | Srinivasan Murugesan | Xu Zhang | Xiangrong Zhang | Hongxia Xu
We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1<em>H</em>)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in <em>in vitro</em> and <em>in vivo</em> models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis,<em> </em>and caused cell cycle arrest <em>in vitro</em>. It inhibited the growth of xenograft tumors with minimal host toxicity. To facilitate future preclinical and clinical development of the agent, we also developed and validated a Rapid Resolution Liquid Chromatography (RRLC) method for quantitative analysis of FBA-TPQ in plasma and tissue samples. The method was found to be precise, accurate, and specific. Using this method, we carried out <em>in vitro</em> and <em>in vivo</em> evaluations of the pharmacological properties of FBA-TPQ, including stability in plasma, plasma protein binding, metabolism by S9 enzymes, plasma pharmacokinetics, and tissue distribution. Our results indicate that FBA-TPQ is a potential therapeutic agent for pancreatic cancer, providing a basis for future preclinical and clinical development.
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