A pharmaceutical composition comprising a HDAC inhibitor and a steroid and the use thereof
a technology of hdac inhibitor and steroid, which is applied in the direction of tetrapeptide ingredients, cyclic peptide ingredients, depsipeptide ingredients, etc., can solve the problems of cell clone that does not respect the integrity of other cells and tissues, and eventually metastasizes, so as to improve the survival of patients.
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example 1
Valproic Acid (VPA) Sensitises DLBCL Cell Lines to CHOP Treatment
[0059]The DLBCL cell lines WSU-NHL, Karpas-422, ULA, SU-DHL-5 and SU-DHL-8 cells were treated for 72 hours with three different concentrations (0.1 mM, 2 mM and 10 mM respectively) of valproic acid (VPA) alone, or in combination with CHOP. The CHOP regimen used in all examples consists of 10 μM cyclophosphamide monohydrate, 20 nM doxorubicin hydrochloride, 2 nM vincristine sulfate and 20 μg / ml prednisolone. (Ageberg, Rydström, Lindén, Linderoth, Jerkeman and Drott; Exp Cell Research; May 1; 317(8):1179-91).
[0060]The cell viability was assessed after 72 hours by trypan blue exclusion and normalised to untreated control cells at day 0 (seeding). Data are presented as mean±SEM, n=3.
[0061]As shown in Table 1, addition of valproic acid increased the cell death in response to CHOP treatment in all lymphoma cell lines, shows that a combination of valproic acid and CHOP could be beneficial to lymphoma patients.
TABLE 1VPA−CHOP+...
example 2
Physiologically Relevant Concentrations of Valproic Acid (VPA) Sensitises DLBCL Cell Lines to CHOP Treatment
[0062]The DLBCL cell lines SU-DHL-8 (Table 2A) and WSU-NHL (Table 2B) were treated for 72 hours with 0.5 mM or 1.5 mM VPA alone, or in combination with CHOP. The concentration of 0.5 mM VPA was chosen because it is a normal serum concentration during continuous VPA treatment in patients with epilepsy. The concentration of 1.5 mM VPA was chosen because it is the maximal tolerated serum concentration during 5 day VPA treatment for compassionate use as noted by the inventor.
[0063]The cell viability was assessed after 0 (Day 1), 24 (Day 2), 48 (Day 3) and 72 (Day 4) hours respectively, by trypan blue exclusion and normalised to untreated control cells. Data are presented as mean, n=3.
[0064]Treatment effects on viability were tested against the effects of CHOP treatment alone. Significant differences were evaluated using Student's unpaired t-test. All tests were two-sided. Effects ...
example 3
Valproic Acid (VPA) does not Interfere with Rituximab-Mediated Cellular Cytotoxicity
[0067]To estimate the impact of VPA on the antibody-dependent-cellular cytotoxicity (ADCC) induced by the CD20 antibody Rituximab. WSU-NHL cells (Table 3A and 3B) or SU-DHL-8 cells (Table 3C and 3D) were labelled with PKH26, either left untreated or incubated with 1.5 mM VPA for 24 hours followed by addition of rituximab at 0, 0.1, or 10 μg / ml
[0068]NK cells were added as an effector to target cell ratio of 10:1, thereafter the cells were incubated for an additional 20 hours. Dead target cells were identified as double positive for PKH26 and 7-AAD and used as readout of the assay. The data shown demonstrate percentage of dead cells, and representative of two independent experiments. The date show that VPA does not affect Rituximab induced ADCC, compatible with the use of VPA together with CD20 antibodies in lymphoma parients.
TABLE 3AWSU-NHL cellsAmount of+NK Cells +Rituximab+NK cells1.5 mM VPA(μg / ml)M...
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