title: Potentiation of a topoisomerase I inhibitor, karenitecin, by the histone deacetylase inhibitor valproic acid in melanoma: translational and phase I/II clinical trial.
abstract: OBJECTIVE
  The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma.
  
  
  METHODS
  Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function.
  
  
  RESULTS
  VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VPA was 75 mg/kg/d; at maximum tolerated dose, serum VPA was approximately 200 microg/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose.
  
  
  CONCLUSIONS
  VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.
authors.affiliation: Experimental Therapeutics Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. adaud@medicine.ucsf.edu
authors.forename: Adil I
authors.initials: AI
authors.lastname: Daud
authors.forename: Jana
authors.initials: J
authors.lastname: Dawson
authors.forename: Ronald C
authors.initials: RC
authors.lastname: DeConti
authors.forename: Elona
authors.initials: E
authors.lastname: Bicaku
authors.forename: Douglas
authors.initials: D
authors.lastname: Marchion
authors.forename: Sem
authors.initials: S
authors.lastname: Bastien
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Hausheer
authors.forename: Richard
authors.initials: R
authors.lastname: Lush
authors.forename: Anthony
authors.initials: A
authors.lastname: Neuger
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster