330 FLUORINATION OF ENIGMOL IMPROVES TISSUE UPTAKE AND AFFECTS IN VIVO PROSTATE CANCER EFFICACY (2013)

You have accessJournal of UrologyProstate Cancer: Basic Research (II)1 Apr 2013330 FLUORINATION OF ENIGMOL IMPROVES TISSUE UPTAKE AND AFFECTS IN VIVOPROSTATE CANCER EFFICACY Suzanne G. Mays, Mark T. Baillie, Eric J. Miller, Anatoliy S. Bushnev, Sarah T. Pruett, Deborah G. Culver, Taylor J. Evers, Jingjing Gao, G. Prakabahr Reddy, Michael G. Natchus, Richard F. Arrendale, Randy B. Howard, Dennis C. Liotta, and John A. Petros Suzanne G. MaysSuzanne G. Mays Atlanta, GA More articles by this author , Mark T. BaillieMark T. Baillie Atlanta, GA More articles by this author , Eric J. MillerEric J. Miller Atlanta, GA More articles by this author , Anatoliy S. BushnevAnatoliy S. Bushnev Atlanta, GA More articles by this author , Sarah T. PruettSarah T. Pruett Atlanta, GA More articles by this author , Deborah G. CulverDeborah G. Culver Atlanta, GA More articles by this author , Taylor J. EversTaylor J. Evers Atlanta, GA More articles by this author , Jingjing GaoJingjing Gao Atlanta, GA More articles by this author , G. Prakabahr ReddyG. Prakabahr Reddy Atlanta, GA More articles by this author , Michael G. NatchusMichael G. Natchus Atlanta, GA More articles by this author , Richard F. ArrendaleRichard F. Arrendale Atlanta, GA More articles by this author , Randy B. HowardRandy B. Howard Atlanta, GA More articles by this author , Dennis C. LiottaDennis C. Liotta Atlanta, GA More articles by this author , and John A. PetrosJohn A. Petros Atlanta, GA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1715AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Previous preclinical studies have established that the novel sphingosine analog, Enigmol ([2S,3S,5S]-2-amino-3,5-dihydroxyoctadecane), inhibits growth of prostate tumors. Fluorination of Enigmol was hypothesized to improve uptake by increasing drug hydrophobicity, which could lead to greater efficacy. The objectives of these studies were to investigate pharmacokinetics and in vivoefficacy of two fluorinated Enigmol analogs, called analogs A and B(structures to be revealed at the meeting). METHODS PK studies used male Sprague-Dawley rats (n=4) given a single oral dose of Enigmol or analog (10 mg/kg). Two xenograft studies were conducted, each of which compared a fluorinated analog to Enigmol. Nude mice with established subcutaneous PC3 xenografts were gavaged daily with vehicle, Enigmol, or either A (exp. 1) or B (exp. 2), (10 mg/kg; n=10-11). Tumor sizes and body weights were monitored over time. Significance of differences in tumor growth was assessed by linear mixed model for repeated measurements: p<0.05 was considered significant. Drug levels in plasma, several normal tissues (PK), and tumor tissues (exp. 2) were quantified by mass spectrometry. RESULTS Both fluorinated analogs reached higher plasma concentrations than Enigmol (A, 40+/− 11 ng/ml; B, 67 +/− 6; Enigmol, 25+/− 2 ng/ml) and accumulated at higher levels than Enigmol in all normal tissues examined (for example, in prostate: A, 23+/− 9; B, 12 +/− 4; Enigmol, 0.27 +/− 0.08 μg/g after 24 hours). A caused statistically significantly slower tumor growth rates than vehicle or Enigmol (p=0.0002 vs vehicle; p=0.04 vs Enigmol, Fig. 1). In the second xenograft study, Enigmol slowed tumor growth rate compared to controls (p=0.02), but B did not (p=0.17), although tumor drug levels at the end of the study were ∼5-fold higher than in the Enigmol group. Mice treated with B lost weight (12%), suggesting host toxicity. Weight loss was not seen with any other groups in these studies. CONCLUSIONS Fluorination of Enigmol improved uptake and tissue distribution as hypothesized. The two fluorinated analogs had differing effects on tumor growth rates of PC3 xenografts: B was less effective than Enigmol, while A was superior. The increased efficacy and apparent lack of toxicity of A are notable and suggest that this analog has therapeutic potential. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e133-e134 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Suzanne G. Mays Atlanta, GA More articles by this author Mark T. Baillie Atlanta, GA More articles by this author Eric J. Miller Atlanta, GA More articles by this author Anatoliy S. Bushnev Atlanta, GA More articles by this author Sarah T. Pruett Atlanta, GA More articles by this author Deborah G. Culver Atlanta, GA More articles by this author Taylor J. Evers Atlanta, GA More articles by this author Jingjing Gao Atlanta, GA More articles by this author G. Prakabahr Reddy Atlanta, GA More articles by this author Michael G. Natchus Atlanta, GA More articles by this author Richard F. Arrendale Atlanta, GA More articles by this author Randy B. Howard Atlanta, GA More articles by this author Dennis C. Liotta Atlanta, GA More articles by this author John A. Petros Atlanta, GA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...