Abstract 1826: Bioavailability, pharmacodynamics and safety profile of a novel anti-angiogenic compound JFD in pre-clinical models
Authors: Sivanesan Dhandayuthapani, Thanigaivelan Kanagasabai, Khadija Cheema, Appu Rathinavelu
Journal: Cancer Research (2017)

Abstract JFD, isoindole (1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl)-amide, is a small molecule that was developed using molecular modeling to specifically antagonize Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and associated kinase activity, thereby producing anti-angiogenic and anti-cancer effects. Since the original form of JFD is hydrophobic, it was recently modified into a water soluble form (JFD-WS) to increase its water solubility and bioavailability. Initially, we investigated the in vitro pharmacodynamics effect of both JFD and JFD-WS by utilizing Matrigel® tube formation assays, scratch and cell migration assays followed by inhibition of VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs). In vivo tumor growth inhibition of JFD and JFD-WS was tested using GI-101A breast adenocarcinoma cells implanted xenograft animals. Subsequently, the blood samples and the tumor proteins were extracted from the control and experimental animals to measure the pro-apoptotic signals and the levels of plasma biomarker such as MUC1 (mucin 1). The safety profile was established using Balb-c mice that were injected intraperitoneally (i.p) with JFD (6 mg/Kg body weight) and JFD-WS (100 mg/Kg body weight) for 30 days. The pharmacokinetics (PK) of JFD including the plasma concentration, excretion, elimination and distribution in the experimental animals were analyzed using a simple HPLC method. As expected, the JFD effectively inhibited HUVECs migration, tube formation, and VEGFR2 phosphorylation. Moreover, both JFD and JFD-WS exhibited strong anti-tumorigenic effects in xenograft implanted experimental animals that were evidenced by the decreasing plasma levels of MUC1. The western blot analysis of apoptotic markers and DNA fragmentation analysis further confirmed the pro-apoptotic effects of JFD as well as JFD-WS in our experimental system. Following i.p. injection, there was a significant distribution of JFD original into the liver, kidney, and brain, which contained the highest concentration compared to other two organs. When hematological, hepatic, renal and cardiac function markers were analyzed in the experimental animals, that were treated with JFD-WS for four weeks, no significant alterations were found in the test group compared to the control animals. Thus, whether used as a single agent or in combination with the other anti-cancer drugs, JFD shows strong antitumor effects without producing severe toxicities. The efficient delivery of JFD original to the brain suggests that this drug would be useful in treating solid tumors of the brain with pro-angiogenic abilities. (This project was supported by the Community Foundation of Broward, Ft. Lauderdale, FL and The Royal Dames of Cancer Research Inc., Ft. Lauderdale, FL). Note: This abstract was not presented at the meeting. Citation Format: Sivanesan Dhandayuthapani, Thanigaivelan Kanagasabai, Khadija Cheema, Appu Rathinavelu. Bioavailability, pharmacodynamics and safety profile of a novel anti-angiogenic compound JFD in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1826. doi:10.1158/1538-7445.AM2017-1826