Methods of inducing terminal differentiation

Abstract

The present invention provides methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylase (HDAC) by administration of pharmaceutical compositions comprising potent HDAC inhibitors. The oral bioavailability of the active compounds in the pharmaceutical compositions of the present invention is surprisingly high. Moreover, the pharmaceutical compositions unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo.

1 . A method of producing a mean plasma concentration of suberoylanilide hydroxamic acid (SAHA) of at least about 10 nM and less than about 5 μM in vivo in a patient at 2 hours following administration, which comprises orally administering to said patient an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof as the active ingredient, and a pharmaceutically acceptable carrier or diluent.  
     
     
         2 .- 159 . (canceled)  
     
     
         160 . The method according to  claim 1 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 100 nM and less than about 1 μM in vivo at 2 hours following administration.  
     
     
         161 . The method according to  claim 1 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo at 8 hours following administration.  
     
     
         162 . The method according to  claim 160 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo at 8 hours following administration.  
     
     
         163 . The method according to  claim 1 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 100 nM in vivo at 8 hours following administration.  
     
     
         164 . The method according to  claim 160 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 100 nM in vivo at 8 hours following administration.  
     
     
         165 . The method according to  claim 161 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo at 12 hours following administration.  
     
     
         166 . The method according to  claim 162 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo at 12 hours following administration.  
     
     
         167 . The method according to  claim 163 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo at 12 hours following administration.  
     
     
         168 . The method according to  claim 164 , wherein said pharmaceutical composition provides a mean plasma concentration of SAHA of at least about 10 nM in vivo at 12 hours following administration.  
     
     
         169 . The method according to  claim 1 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         170 . The method according to  claim 160 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         171 . The method according to  claim 161 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         172 . The method according to  claim 162 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         173 . The method according to  claim 163 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         174 . The method according to  claim 164 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         175 . The method according to  claim 165 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         176 . The method according to  claim 167 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         177 . The method according to  claim 168 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 400 mg once a day.  
     
     
         178 . The method according to  claim 1 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 200 mg once a day.  
     
     
         179 . The method according to  claim 160 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 200 mg once a day.  
     
     
         180 . The method according to  claim 161 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 200 mg once a day.  
     
     
         181 . The method according to  claim 162 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 200 mg once a day.  
     
     
         182 . The method according to  claim 163 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 200 mg once a day.  
     
     
         182 . The method according to  claim 164 , wherein the pharmaceutical composition comprises SAHA as the active ingredient, and is administered 200 mg once a day.