Schneider B.J.,New York Medical College |
Kalemkerian G.P.,University of Michigan |
Kalemkerian G.P.,500 dical Center Drive |
Bradley D.,Duke University |
And 9 more authors.
Investigational New Drugs | Year: 2012
Introduction Vorinostat is an inhibitor of histone deacetylase 6, which acetylates tubulin and stabilizes microtubules. Since taxanes also stabilize microtubules, we hypothesized that the administration of vorinostat followed by docetaxel should result in synergistic cytotoxicity. We conducted a phase I trial to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in =30%of patients. Methods Eligible patients had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after =1 prior chemotherapy regimen not containing docetaxel, performance status of 0-2, and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle, with docetaxel given intravenously over 1 h on day 4. The time-to-event continuous reassessment method (TITE-CRM) guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Pharmacokinetic studies were performed on days 1 and 4 of cycle 1. Results Twelve patients were enrolled: median age 65 years (range 49-74); 9 male, 3 female; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles administered was 2. Two patients were treated at DL -1, 4 at DL 0, 5 atDL 1 and 1 at DL 2. Five DLTs occurred in 5 patients: neutropenic fever/sepsis (2), anaphylactic reaction (1), myocardial infarction (1) and gastrointestinal bleed (1). Other toxicities included grade 3/4 neutropenia (4), peripheral neuropathy (1), and gastrointestinal bleed (n=1). The estimated probability of DLT for DL -1 was 0.32 (90% posterior probability interval [PI], 0.11 to 0.53) for DL 0, 0.38 (90% PI, 0.16 to 0.58) and for DL 1, 0.43 (90% PI, 0.23 to 0.64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions The combination of vorinostat and docetaxel was poorly tolerated with excessive DLTs that required early study termination. No responses were identified. Vorinostat and docetaxel pharmacokinetics were comparable to previous reports in the literature, without obvious drug-drug interactions. © Springer Science+Business Media, LLC 2010.
Chattopadhyay M.,University of Michigan |
Zhou Z.,University of Michigan |
Zhou Z.,University of North Carolina at Chapel Hill |
Hao S.,University of Michigan |
And 4 more authors.
Molecular Pain | Year: 2012
Background: Painful neuropathy is a common complication of diabetes. Previous studies have identified significant increases in the amount of voltage gated sodium channel isoforms NaV1.7 and NaV1.3 protein in the dorsal root ganglia (DRG) of rats with streptozotocin (STZ)-induced diabetes. We found that gene transfer-mediated release of the inhibitory neurotransmitters enkephalin or gamma amino butyric acid (GABA) from DRG neurons in diabetic animals reduced pain-related behaviors coincident with a reduction in NaV1.7 protein levels in DRG in vivo. To further evaluate the role of NaVα subunit levels in DRG in the pathogenesis of pain in diabetic neuropathy, we constructed a non-replicating herpes simplex virus (HSV)-based vector expressing a microRNA (miRNA) against NaVα subunits.Results: Subcutaneous inoculation of the miRNA-expressing HSV vector into the feet of diabetic rats to transduce DRG resulted in a reduction in NaVα subunit levels in DRG neurons, coincident with a reduction in cold allodynia, thermal hyperalgesia and mechanical hyperalgesia.Conclusions: These data support the role of increased NaVα protein in DRG in the pathogenesis of pain in diabetic neuropathy, and provide a proof-of-principle demonstration for the development of a novel therapy that could be used to treat intractable pain in patients with diabetic neuropathy. © 2012 Chattopadhyay et al; licensee BioMed Central Ltd.
Vainshtein J.M.,1500 dical Center Drive |
Spector M.E.,University of Michigan |
Stenmark M.H.,1500 dical Center Drive |
Bradford C.R.,University of Michigan |
And 7 more authors.
Oral Oncology | Year: 2014
Objectives: Although widely adopted, the accuracy of post-chemoradiotherapy (CRT) 18F-fluorodeoxygluocose positron emission tomography/computed tomography (PET/CT) for predicting locoregional failure (LRF) in human papillomavirus-related (HPV+) oropharyngeal cancer (OPC) remains poorly characterized. We assessed the predictive value of 3-month PET/CT response for LRF in this population. Materials and methods: 101 consecutive patients with stage III-IV HPV+ OPC who underwent definitive CRT with pre-treatment and 3-month post-CRT PET/CT at our institution from 3/2005-3/2011 were included. 3-month PET/CT response was re-classified as complete-response (CR), near-CR, or incomplete-response (