In cases like this when there is a tie in efficacy, the highest dose should be selected, and hence we have selected the dose of 40 mg Kg for our phase II Axitinib side effects studies. Currently, there is no information concerning the effect of HDAC inhibitors upon acetylation of H3 and H4 in solid tumors of patients. Two reports on depsipeptide have demonstrated hyperacetylation of PBMN cells in two patients with cutaneous T cell lymphoma and two patients with refractory neoplasms as evaluated by immunoflouorescent labelling, additionally, in a clinical study of SAHA for lymphoma and solid tumors it was reported that three of five patients showed increased accumulation of acetylated H3 in the post treatment biopsy sample. These data are in agreement with our findings indicating that the hyperacetylating effect is clin ically achievable with these HDAC inhibitors.
The inhibitory activity of HDAC in cells shown by this class of compounds always parallels changes in H3 and H4 acetylation. We demonstrate herein that valproic acid produces a decrease in HDAC activity in tumors which is accompanied by histone hyperacetylation sug gesting that the H3 and H4 hyperacetylation occurring in tumors is a consequence of HDAC inhibition. On the other hand, it is remarkable that three out of the four cases assayed by H3 and H4 acetylation by western blot in PBMN cells their corresponding tumors had hyperacetylation showing the concordance between the findings in tumors and PBMN cells. These data suggest that HDAC activity in the tumor or H3 and H4 acetylation status in the PBMN cells can be good sur rogate markers for monitoring the effect of HDAC inhibi tors in clinical trials.
The pharmacokinetics of valproic acid has extensively been studied. Because its half life is between 8 16 hours, the steady state concentrations can be determined as soon as at day 4 of treatment. Under this rational we determined the levels of valproic acid at day six, within 8 10 hours of the last dose taken, hence the sera values obtained are representative of the levels at the steady state. High interindividual variation in the pharmacoki netics of valproic acid in epileptic patients is well known. This phenomenon was observed in our study with serum concentrations ranging from 73. 61 to 170. 49 g mL, and in addition there was no correlation with dose level and mean concentration achieved.
thus, for doses of 20, 30, and 40 mg kg, mean concentrations were 94. 06, 123. 46, and 90. 93 g mL, respectively. This finding, how ever, could be derived from the small number of patients we analyzed, because Tisdale et al. demonstrated signifi cant linear correlation between Cilengitide VPA dose and serum con centration in a sample of 60 epileptic patients. Alternatively, it can be suggested that like in cell lines, which show high variability in response to HDAC inhibi tors, interpatient variability in tumors may exist.
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