A Pilot , First-inHuman , Pharmacokinetic Study of 9 cUAB 30 in Healthy Volunteers

9cUAB30 is a synthetic analog of 9-cis-retinoic acid with chemopreventive activity in cell lines and in animal models. The purpose of this first-in-human evaluation of 9cUAB30 was to evaluate the single-dose pharmacokinetic profile and toxicity of the compound in healthy volunteers at 3 dose levels. This study enrolled 14 patients to receive a single dose of 5, 10, or 20 mg of 9cUAB30. Plasma and urine samples were collected to assess 9cUAB30 concentrations by a validated LC/MSMSmethod. 9cUAB30was well tolerated, with 1 patient experiencing grade 2 toxicity and no grade 3 or 4 toxicities reported. Tmax occurred approximately 3 hours after dose administration with the plasma half-life ranging from 2.79 to 7.21 hours. AUC increased linearly across the examined dose range of 5 to 20 mg; Cmax was proportional to the log of the dose. The plasma clearance ranged from 25 to 39 L/h compared to the renal clearance which ranged from 0.018 to 0.103 L/h. 9cUAB30 has a favorable toxicity and pharmacokinetic profile, with oral availability and primarily hepatic metabolism. Further dose ranging studies with once a day dosing are underway. Cancer Prev Res; 3(12); 1565–70. 2010 AACR.

[1]  K. Bland,et al.  Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers. , 2006, Carcinogenesis.

[2]  K. Bland,et al.  Conformationally defined retinoic acid analogues. 5. Large-scale synthesis and mammary cancer chemopreventive activity for (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9cUAB30). , 2003, Journal of medicinal chemistry.

[3]  I. Kapetanovic,et al.  In vitro assessment of P450 induction potential of novel chemopreventive agents SR13668, 9-cis-UAB30, and pentamethychromanol in primary cultures of human hepatocytes. , 2009, Chemico-biological interactions.

[4]  K. Bland,et al.  9cUAB30, an RXR specific retinoid, and/or tamoxifen in the prevention of methylnitrosourea-induced mammary cancers. , 2003, Cancer letters.

[5]  J. Brtko,et al.  Renaissance of the biologically active vitamin A derivatives: established and novel directed therapies for cancer and chemoprevention. , 2003, Current pharmaceutical design.

[6]  L. D. De Luca,et al.  Therapeutic potential of "rexinoids" in cancer prevention and treatment. , 2009, Cancer research.

[7]  V. Vivat-Hannah,et al.  Selective retinoids and rexinoids in cancer therapy and chemoprevention. , 2002, Drug discovery today.

[8]  M. Kane,et al.  Quantitative profiling of endogenous retinoic acid in vivo and in vitro by tandem mass spectrometry. , 2008, Analytical chemistry.

[9]  T. Tollefsbol,et al.  The low-toxicity 9-cis UAB30 novel retinoid down-regulates the DNA methyltransferases and has anti-telomerase activity in human breast cancer cells. , 2007, International journal of oncology.

[10]  J. Berletch,et al.  The Novel Retinoid, 9cUAB30, Inhibits Telomerase and Induces Apoptosis in HL60 Cells. , 2008, Translational oncology.

[11]  J. Ruppert,et al.  Prevention of KLF4-mediated tumor initiation and malignant transformation by UAB30 rexinoid , 2009, Cancer biology & therapy.

[12]  D. Serrano,et al.  Clinical trials with retinoids for breast cancer chemoprevention. , 2006, Endocrine-related cancer.

[13]  D. Crowe,et al.  A retinoid X receptor (RXR)-selective retinoid reveals that RXR-α is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands , 2004, Breast Cancer Research.

[14]  M. Taimi,et al.  Conformationally defined retinoic acid analogues. 4. Potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias. , 1998, Journal of medicinal chemistry.