cytotoxic activity in combination with GCV comparable to 2 or 3 day exposure. These findings suggest that prolonged exposure Neohesperidin to HDAC inhibitors might not be necessary in the clinical setting, potentially limiting secondary toxicities. Indeed, we have reported previously that shorter durations of exposure to butyrate also efficiently killed EBV lymphoma cells in the presence of GCV.33 Based on these data, 1 patient with refractory EBV lymphoma was treated in a protocol using butyrate for 5 days and GCV or valganciclovir for 21 days, and the lymphoma burden was dramatically reduced within 1 cycle. Furthermore, previously high EBV viral loads, as well as the viral loads of 2 other herpesviruses , became undetectable.39 The reported pharmacokinetics and pharmacodynamics for MS275 and LBH589 as single agents appear superior to butyrate.
A phase 1 clinical trial with MS275 administered orally demonstrated that the area under the plasma concentration versus time curve easily reached 59 268 ng/h/mL for doses of 2 8 mg/m2 and was sustained for a minimum of 34 26 hours across all dose levels.40 Fulvestrant molecular weight The administration of MS275 induced acetylation of histone H3 and H4 in circulating PBMCs in these studies and in a variety of tumor cell lines, including prostate, Vinorelbine price pancreas, and breast cancer lines, at these concentrations in vitro.41 LBH589 also displayed rapid absorption when administered orally in a phase 1 clinical trial, with a serum half life of approximately 14.6 hours and an area under the curve of 134 ng/h/mL for a single 20 mg dose.
42 The results of the present study Marbofloxacin ic50 demonstrate that the EBV latency type in the lymphoma is not crucial for the success of combination therapy approach with HDAC inhibitors and GCV. P3HR1 cells, a line originally derived from the BL cell line Jijoye, produce virus particles that are transformation defective.43 Daudi cells were also isolated from a BL patient and are a transformationdefective but EBV nonproducing line.44 Our data demonstrate that the inherent viral defects of the P3HR1 or Daudi cells do not interfere with HDAC inhibitor–mediated induction of lytic phase gene expression and cytotoxicity in the presence of an antiherpes viral drug. The JY cell line, an EBV transformed LCL with a different latency pattern, responded equally well to the combination treatment approach with either butyrate or LBH589 as the viral inducing agent.
These results in the nursing model JY cell line mirror the observed responsiveness of PTLD patients to the combination of butyrate and GCV in a previous clinical trial.18 PTLD, commonly arising in immunosuppressed individuals, is caused by unchecked proliferation of EBV B cells in the absence of immune surveillance. In both LCL and PTLD, EBV maintains a type 3 latency in which all of the EBV latent gene products are expressed. In summary, the results of the present study demonstrate that several structurally distinct HDAC inhibitors are efficient agents for sensitizing EBV lymphoma cells to antiherpes virus drugs. Only nanomolar concentrations of the most potent of these agents are necessary for optimal effect. Our previous work demonstrated that the HDAC inhibitor butyrate has impressive early phase clinical activity in the treatment of patients with EBV lymphomas, and data from the present study.