Chiao, Judy H. (Berkeley Heights, NJ, US)
Bacopoulos, Nicholas G. (New York, NY, US)
Miller, Thomas A. (New York, NY, US)
Paradise, Carolyn M. (Cortland Manor, NY, US)
Richon, Victoria M. (Rye, NY, US)

Plaque It!

10/616649

07/01/2004

07/09/2003

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514/352

514/575

(IPC1-7): A61K031/19; A61K031/44

MINTZ LEVIN COHN FERRIS GLOVSKY & POPEO (666 THIRD AVENUE, NEW YORK, NY, 10017, US)

What is claimed is:

1. A method of treating cutaneous T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 57 and a pharmaceutically acceptable carrier or diluent, wherein the amount of SAHA is effective to treat cutaneous T-cell lymphoma in said subject.

2. A method of treating cutaneous T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising pyroxamide or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 58 and a pharmaceutically acceptable carrier or diluent, wherein the amount of pyroxamide is effective to treat cutaneous t-cell lymphoma in said subject.

3. A method of treating cutaneous T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 59 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8, and a pharmaceutically acceptable carrier or diluent, wherein the amount of histone deacetylase inhibitor is effective to treat the cutaneous T-cell lymphoma in said subject.

4. A method of treating cutaneous T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 60 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8, and a pharmaceutically acceptable carrier or diluent, wherein the amount of histone deacetylase inhibitor is effective to treat the cutaneous T-cell lymphoma in said subject.

5. A method of treating cutaneous T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 61 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10, and a pharmaceutically acceptable carrier or diluent, wherein the amount of histone deacetylase inhibitor is effective to treat the cutaneous T-cell lymphoma in said subject.

6. The method of claim 1, wherein the pharmaceutical composition is administered orally.

7. The method of claim 6, wherein said composition is contained within a gelatin capsule.

8. The method of claim 7, wherein said carrier or diluent is microcrystalline cellulose.

9. The method of claim 8, further comprising sodium croscarmellose as a disintegrating agent.

10. The method of claim 9, further comprising magnesium stearate as a lubricant.

11. The method of claim 1, wherein said composition is administered to the subject at a total daily dosage of between about 25-4000 mg/m².

12. The method of claim 6, wherein said composition is administered once-daily, twice-daily or three times-daily.

13. The method of claim 12, wherein said composition is administered once daily at a dose of about 200-600 mg.

14. The method of claim 12, wherein said composition is administered twice daily at a dose of about 200-400 mg.

15. The method of claim 12, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

16. The method of claim 15, wherein said composition is administered twice daily three to five days per week.

17. The method of claim 16, wherein said composition is administered twice daily three days a week.

18. The method of claim 17, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

19. The method of claim 17, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

20. The method of claim 2, wherein the pharmaceutical composition is administered orally.

21. The method of claim 20, wherein said composition is contained within a gelatin capsule.

22. The method of claim 21, wherein said carrier or diluent is microcrystalline cellulose.

23. The method of claim 22, further comprising sodium croscarmellose as a disintegrating agent.

24. The method of claim 23, further comprising magnesium stearate as a lubricant.

25. The method of claim 2, wherein said composition is administered to the subject at a total daily dosage of between about 25-4000 mg/m².

26. The method of claim 20, wherein said composition is administered once-daily, twice-daily or three times-daily.

27. The method of claim 26, wherein said composition is administered once daily at a dose of about 200-600 mg.

28. The method of claim 26, wherein said composition is administered twice daily at a dose of about 200-400 mg.

29. The method of claim 26, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

30. The method of claim 29, wherein said composition is administered twice daily three to five days per week.

31. The method of claim 30, wherein said composition is administered twice daily three days a week.

32. The method of claim 31, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

33. The method of claim 31, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

34. A method of treating cutaneous T-cell lymphoma in a subject, which method comprises the step of administering to the subject a total daily dose of up to about 800 mg of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 62 and a pharmaceutically acceptable carrier or diluent, wherein the cutaneous T-cell lymphoma in a subject is treated.

35. The method of claim 34, wherein said composition is administered orally.

36. The method of claim 35, wherein said composition is contained within a gelatin capsule.

37. The method of claim 36, wherein said carrier or diluent is microcrystalline cellulose.

38. The method of claim 37, further comprising sodium croscarmellose as a disintegrating agent.

39. The method of claim 38, further comprising magnesium stearate as a lubricant.

40. The method of claim 35, wherein said composition is administered once-daily, twice-daily or three times-daily.

41. The method of claim 40, wherein said composition is administered once daily at a dose of about 200-600 mg.

42. The method of claim 40, wherein said composition is administered twice daily at a dose of about 200-400 mg.

43. The method of claim 40, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

44. The method of claim 43, wherein said composition is administered twice daily three to five days per week.

45. The method of claim 44, wherein said composition is administered twice daily three days a week.

46. The method of claim 45, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

47. The method of claim 45, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

48. A method of treating peripheral T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 63 and a pharmaceutically acceptable carrier or diluent, wherein the amount of SAHA is effective to treat the peripheral T-cell lymphoma in said subject.

49. A method of treating peripheral T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising pyroxamide or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 64 and a pharmaceutically acceptable carrier or diluent, wherein the amount of pyroxamide is effective to treat the peripheral T-cell lymphoma in said subject.

50. A method of treating peripheral T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 65 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8, and a pharmaceutically acceptable carrier or diluent, wherein the amount of the histone deacetylase inhibitor is effective to treat the peripheral T-cell lymphoma in said subject.

51. A method of treating peripheral T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 66 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8, and a pharmaceutically acceptable carrier or diluent, wherein the amount of the histone deacetylase inhibitor is effective to treat the peripheral T-cell lymphoma in said subject.

52. A method of treating peripheral T-cell lymphoma in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 67 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10, and a pharmaceutically acceptable carrier or diluent, wherein the amount of the histone deacetylase inhibitor is effective to treat the peripheral T-cell lymphoma in said subject.

53. The method of claim 48, wherein the pharmaceutical composition is administered orally.

54. The method of claim 53, wherein said composition is contained within a gelatin capsule.

55. The method of claim 54, wherein said carrier or diluent is microcrystalline cellulose.

56. The method of claim 55, further comprising sodium croscarmellose as a disintegrating agent.

57. The method of claim 56, further comprising magnesium stearate as a lubricant.

58. The method of claim 48, wherein said composition is administered to the subject at a total daily dosage of between about 25-4000 mg/m².

59. The method of claim 53, wherein said composition is administered once-daily, twice-daily or three times-daily.

60. The method of claim 53, wherein said composition is administered once daily at a dose of about 200-600 mg.

61. The method of claim 53, wherein said composition is administered twice daily at a dose of about 200-400 mg.

62. The method of claim 53, wherein said composition is administered twice daily at a dose of 200-400 mg intermittently.

63. The method of claim 62, wherein said composition is administered twice daily three to five days per week.

64. The method of claim 63, wherein said composition is administered twice daily three days a week.

65. The method of claim 64, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

66. The method of claim 64, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

67. The method of claim 49, wherein the pharmaceutical composition is administered orally.

68. The method of claim 67, wherein said composition is contained within a gelatin capsule.

69. The method of claim 68, wherein said carrier or diluent is microcrystalline cellulose.

70. The method of claim 69, further comprising sodium croscarmellose as a disintegrating agent.

71. The method of claim 70, further comprising magnesium stearate as a lubricant.

72. The method of claim 49, wherein said composition is administered to the subject at a total daily dosage of between about 25-4000 mg/m².

73. The method of claim 67, wherein said composition is administered once-daily, twice-daily or three times-daily.

74. The method of claim 73, wherein said composition is administered once daily at a dose of about 200-600 mg.

75. The method of claim 73, wherein said composition is administered twice daily at a dose of about 200-400 mg.

76. The method of claim 75, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

77. The method of claim 76, wherein said composition is administered twice daily three to five days per week.

78. The method of claim 77, wherein said composition is administered twice daily three days a week.

79. The method of claim 78, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

80. The method of claim 78, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

81. A method of treating peripheral T-cell lymphoma in a subject, which method comprises the step of administering to the subject a total daily dose of up to about 800 mg of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 68 and a pharmaceutically acceptable carrier or diluent, wherein the peripheral T-cell lymphoma in a subject is treated.

82. The method of claim 81, wherein said composition is administered orally.

83. The method of claim 82, wherein said composition is contained within a gelatin capsule.

84. The method of claim 83, wherein said carrier or diluent is microcrystalline cellulose.

85. The method of claim 84, further comprising sodium croscarmellose as a disintegrating agent.

86. The method of claim 85, further comprising magnesium stearate as a lubricant.

87. The method of claim 82, wherein said composition is administered once-daily, twice-daily or three times-daily.

88. The method of claim 87, wherein said composition is administered once daily at a dose of about 200-600 mg.

89. The method of claim 87, wherein said composition is administered twice daily at a dose of about 200-400 mg.

90. The method of claim 87, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

91. The method of claim 90, wherein said composition is administered twice daily three to five days per week.

92. The method of claim 91, wherein said composition is administered twice daily three days a week.

93. The method of claim 92, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

94. The method of claim 92, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

95. A method of treating head and neck cancer in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 69 and a pharmaceutically acceptable carrier or diluent, wherein the amount of SAHA is effective to treat the head and neck cancer in said subject.

96. A method of treating head and neck cancer in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising pyroxamide or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 70 and a pharmaceutically acceptable carrier or diluent, wherein the amount of pyroxamide is effective to treat the head and neck cancer in said subject.

97. A method of treating head and neck cancer in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 71 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8, and a pharmaceutically acceptable carrier or diluent, wherein the amount of histone deacetylase inhibitor is effective to treat the head and neck cancer in said subject.

98. A method of treating head and neck cancer in a subject, which method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 72 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8, and a pharmaceutically acceptable carrier or diluent, wherein the amount of histone deacetylase inhibitor is effective to treat the head and neck cancer in said subject.

99. A method of treating head and neck cancer in a subject, said method comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 73 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10, and a pharmaceutically acceptable carrier or diluent, wherein the amount of histone deacetylase inhibitor is effective to treat the head and neck cancer in said subject.

100. The method of claim 95, wherein the pharmaceutical composition is administered orally.

101. The method of claim 100, wherein said composition is contained within a gelatin capsule.

102. The method of claim 101, wherein said carrier or diluent is microcrystalline cellulose.

103. The method of claim 102, further comprising sodium croscarmellose as a disintegrating agent.

104. The method of claim 103, further comprising magnesium stearate as a lubricant.

105. The method of claim 95, wherein said composition is administered to the subject at a total daily dosage of between about 25-4000 mg/m².

106. The method of claim 100, wherein said composition is administered once-daily, twice-daily or three times-daily.

107. The method of claim 106, wherein said composition is administered once daily at a dose of about 200-600 mg.

108. The method of claim 106, wherein said composition is administered twice daily at a dose of about 200-400 mg.

109. The method of claim 106, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

110. The method of claim 109, wherein said composition is administered twice daily three to five days per week.

111. The method of claim 110, wherein said composition is administered twice daily three days a week.

112. The method of claim 111, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

113. The method of claim 111, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

114. The method of claim 95, wherein the head and neck cancer is a squamous cell carcinoma.

115. The method of claim 96, wherein the pharmaceutical composition is administered orally.

116. The method of claim 115, wherein said composition is contained within a gelatin capsule.

117. The method of claim 116, wherein said carrier or diluent is microcrystalline cellulose.

118. The method of claim 117, further comprising sodium croscarmellose as a disintegrating agent.

119. The method of claim 118, further comprising magnesium stearate as a lubricant.

120. The method of claim 96, wherein said composition is administered to the subject at a total daily dosage of between about 25-4000 mg/m².

121. The method of claim 115, wherein said composition is administered once-daily, twice-daily or three times-daily.

122. The method of claim 121, wherein said composition is administered once daily at a dose of about 200-600 mg.

123. The method of claim 121, wherein said composition is administered twice daily at a dose of about 200-400 mg.

124. The method of claim 123, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

125. The method of claim 124, wherein said composition is administered twice daily three to five days per week.

126. The method of claim 125, wherein said composition is administered twice daily three days a week.

127. The method of claim 126, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

128. The method of claim 126, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

129. The method of claim 96, wherein the head and neck cancer is a squamous cell carcinoma.

130. A method of treating head and neck cancer in a subject, which method comprises the step of administering to the subject a total daily dose of up to about 800 mg of a pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof, represented by the structure: 74 and a pharmaceutically acceptable carrier or diluent, wherein the head and neck cancer in a subject is treated.

131. The method of claim 130, wherein said composition is administered orally.

132. The method of claim 131, wherein said composition is contained within a gelatin capsule.

133. The method of claim 132, wherein said carrier or diluent is microcrystalline cellulose.

134. The method of claim 133, further comprising sodium croscarmellose as a disintegrating agent.

135. The method of claim 134, further comprising magnesium stearate as a lubricant.

136. The method of claim 131, wherein said composition is administered once-daily, twice-daily or three times-daily.

137. The method of claim 136, wherein said composition is administered once daily at a dose of about 200-600 mg.

138. The method of claim 136, wherein said composition is administered twice daily at a dose of about 200-400 mg.

139. The method of claim 136, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

140. The method of claim 139, wherein said composition is administered twice daily three to five days per week.

141. The method of claim 140, wherein said composition is administered twice daily three days a week.

142. The method of claim 141, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

143. The method of claim 141, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

144. The method of claim 130, wherein the head and neck cancer is a squamous cell carcinoma.

145. A method of selectively inducing terminal differentiation of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising the step of administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the composition is administered once, twice or three times daily at a total daily dose of up to about 800 mg.

146. The method of claim 145, wherein the pharmaceutical composition is administered orally.

147. The method of claim 146, wherein said composition is contained within a gelatin capsule.

148. The method of claim 147, wherein said carrier or diluent is microcrystalline cellulose.

149. The method of claim 148, further comprising sodium croscarmellose as a disintegrating agent.

150. The method of claim 149, further comprising magnesium stearate as a lubricant.

151. The method of claim 146, wherein said composition is administered once-daily, twice-daily or three times-daily.

152. The method of claim 151, wherein said composition is administered once daily at a dose of about 200-600 mg.

153. The method of claim 151, wherein said composition is administered twice daily at a dose of about 200-400 mg.

154. The method of claim 151, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

155. The method of claim 154, wherein said composition is administered twice daily three to five days per week.

156. The method of claim 155, wherein said composition is administered twice daily three days a week.

157. The method of claim 156, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

158. The method of claim 156, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

159. The method of claim 151, wherein said composition is administered three times a day.

160. The method of claim 159, wherein said composition is administered three times-daily for two consecutive weeks, followed by one week without administration of said composition.

161. The method according to claim 145, wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA): 75

162. The method according to claim 145, wherein said HDAC inhibitor is pyroxamide, represented by the structure: 76

163. The method according to claim 145, wherein said HDAC inhibitor is represented by the structure: 77 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8.

164. The method according to claim 145, wherein said HDAC inhibitor is represented by the structure: 78 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.

165. The method according to claim 145, wherein said HDAC inhibitor is represented by the structure: 79 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.

166. A method of inducing differentiation of tumor cells in a subject having a tumor, said method comprising the step of administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the composition is administered once, twice or three times daily at a total daily dose of up to about 800 mg.

167. The method according to claim 166, wherein the pharmaceutical composition is administered orally.

168. The method according to claim 167, wherein said composition is contained within a gelatin capsule.

169. The method according to claim 168, wherein said carrier or diluent is microcrystalline cellulose.

170. The method according to claim 169, further comprising sodium croscarmellose as a disintegrating agent.

171. The method according to claim 170, further comprising magnesium stearate as a lubricant.

172. The method of claim 167, wherein said composition is administered once-daily, twice-daily or three times-daily.

173. The method of claim 172, wherein said composition is administered once daily at a dose of about 200-600 mg.

174. The method of claim 172, wherein said composition is administered twice daily at a dose of about 200-400 mg.

175. The method of claim 172, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

176. The method of claim 175, wherein said composition is administered twice daily three to five days per week.

177. The method of claim 176, wherein said composition is administered twice daily three days a week.

178. The method of claim 177, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

179. The method of claim 177, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

180. The method of claim 172, wherein said composition is administered three times a day.

181. The method of claim 180, wherein said composition is administered three times-daily for two consecutive weeks, followed by one week without administration of said composition.

182. The method according to claim 166, wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA): 80

183. The method according to claim 166, wherein said HDAC inhibitor is pyroxamide, represented by the structure: 81

184. The method according to claim 166, wherein said HDAC inhibitor is represented by the structure: 82 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8.

185. The method according to claim 166, wherein said HDAC inhibitor is represented by the structure: 83 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.

186. The method according to claim 166, wherein said HDAC inhibitor is represented by the structure: 84 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.

187. A method of selectively inducing cell growth arrest of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising the step of administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the composition is administered once, twice or three times daily at a total daily dose of up to about 800 mg.

188. The method according to claim 187, wherein the pharmaceutical composition is administered orally.

189. The method according to claim 188, wherein said composition is contained within a gelatin capsule.

190. The method according to claim 189, wherein said carrier or diluent is microcrystalline cellulose.

191. The method according to claim 190, further comprising sodium croscarmellose as a disintegrating agent.

192. The method according to claim 191, further comprising magnesium stearate as a lubricant.

193. The method of claim 188, wherein said composition is administered once-daily, twice-daily or three times-daily.

194. The method of claim 193, wherein said composition is administered once daily at a dose of about 200-600 mg.

195. The method of claim 193, wherein said composition is administered twice daily at a dose of about 200-400 mg.

196. The method of claim 195, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

197. The method of claim 196, wherein said composition is administered twice daily three to five days per week.

198. The method of claim 197, wherein said composition is administered twice daily three days a week.

199. The method of claim 198, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

200. The method of claim 198, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

201. The method of claim 193, wherein said composition is administered three times a day.

202. The method of claim 201, wherein said composition is administered three times-daily for two consecutive weeks, followed by one week without administration of said composition.

203. The method according to claim 187, wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA): 85

204. The method according to claim 187, wherein said HDAC inhibitor is pyroxamide, represented by the structure: 86

205. The method according to claim 187, wherein said HDAC inhibitor is represented by the structure: 87 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8.

206. The method according to claim 187, wherein said HDAC inhibitor is represented by the structure: 88 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.

207. The method according to claim 187, wherein said HDAC inhibitor is represented by the structure: 89 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.

208. A method of selectively inducing apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in said subject, said method comprising the step of administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the composition is administered once, twice or three times daily at a total daily dose of up to about 800 mg.

209. The method according to claim 208, wherein the pharmaceutical composition is administered orally.

210. The method according to claim 209, wherein said composition is contained within a gelatin capsule.

211. The method according to claim 210, wherein said carrier or diluent is microcrystalline cellulose.

212. The method according to claim 211, further comprising sodium croscarmellose as a disintegrating agent.

213. The method according to claim 212, further comprising magnesium stearate as a lubricant.

214. The method of claim 209, wherein said composition is administered once-daily, twice-daily or three times-daily.

215. The method of claim 214, wherein said composition is administered once daily at a dose of about 200-600 mg.

216. The method of claim 214, wherein said composition is administered twice daily at a dose of about 200-400 mg.

217. The method of claim 216, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

218. The method of claim 217, wherein said composition is administered twice daily three to five days per week.

219. The method of claim 218, wherein said composition is administered twice daily three days a week.

220. The method of claim 219, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

221. The method of claim 219, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

222. The method of claim 214, wherein said composition is administered three times a day.

223. The method of claim 222, wherein said composition is administered three times-daily for two consecutive weeks, followed by one week without administration of said composition.

224. The method according to claim 208, wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA): 90

225. The method according to claim 208, wherein said HDAC inhibitor is pyroxamide, represented by the structure: 91

226. The method according to claim 208, wherein said HDAC inhibitor is represented by the structure: 92 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8.

227. The method according to claim 208, wherein said HDAC inhibitor is represented by the structure: 93 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.

228. The method according to claim 208, wherein said HDAC inhibitor is represented by the structure: 94 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.

229. A method of treating cancer in a subject in need thereof by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the composition is administered once, twice or three times daily at a total daily dose of up to about 800 mg.

230. The method according to claim 229, wherein the pharmaceutical composition is administered orally.

231. The method according to claim 230, wherein said composition is contained within a gelatin capsule.

232. The method according to claim 231, wherein said carrier or diluent is microcrystalline cellulose.

233. The method according to claim 232, further comprising sodium croscarmellose as a disintegrating agent.

234. The method according to claim 233, further comprising magnesium stearate as a lubricant.

235. The method of claim 230, wherein said composition is administered once-daily, twice-daily or three times-daily.

236. The method of claim 235, wherein said composition is administered once daily at a dose of about 200-600 mg.

237. The method of claim 235, wherein said composition is administered twice daily at a dose of about 200-400 mg.

238. The method of claim 237, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

239. The method of claim 238, wherein said composition is administered twice daily three to five days per week.

240. The method of claim 239, wherein said composition is administered twice daily three days a week.

241. The method of claim 240, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

242. The method of claim 240, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

243. The method of claim 235, wherein said composition is administered three times a day.

244. The method of claim 243, wherein said composition is administered three times-daily for two consecutive weeks, followed by one week without administration of said composition.

245. The method according to claim 229, wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA): 95

246. The method according to claim 229, wherein said HDAC inhibitor is pyroxamide, represented by the structure: 96

247. The method according to claim 229, wherein said HDAC inhibitor is represented by the structure: 97 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8.

248. The method according to claim 229, wherein said HDAC inhibitor is represented by the structure: 98 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.

249. The method according to claim 229, wherein said HDAC inhibitor is represented by the structure: 99 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.

250. A method of chemoprevention in a subject in need thereof by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the composition is administered once, twice or three times daily at a total daily dose of up to about 800 mg.

251. The method according to claim 250, wherein the pharmaceutical composition is administered orally.

252. The method according to claim 251, wherein said composition is contained within a gelatin capsule.

253. The method according to claim 252, wherein said carrier or diluent is microcrystalline cellulose.

254. The method according to claim 253, further comprising sodium croscarmellose as a disintegrating agent.

255. The method according to claim 254, further comprising magnesium stearate as a lubricant.

256. The method of claim 251, wherein said composition is administered once-daily, twice-daily or three times-daily.

257. The method of claim 256, wherein said composition is administered once daily at a dose of about 200-600 mg.

258. The method of claim 256, wherein said composition is administered twice daily at a dose of about 200-400 mg.

259. The method of claim 258, wherein said composition is administered twice daily at a dose of about 200-400 mg intermittently.

260. The method of claim 259, wherein said composition is administered twice daily three to five days per week.

261. The method of claim 260, wherein said composition is administered twice daily three days a week.

262. The method of claim 261, wherein said composition is administered twice daily at a dose of about 200 mg, three days a week.

263. The method of claim 261, wherein said composition is administered twice daily at a dose of about 300 mg, three days a week.

264. The method of claim 256, wherein said composition is administered three times a day.

265. The method of claim 264, wherein said composition is administered three times-daily for two consecutive weeks, followed by one week without administration of said composition.

266. The method according to claim 250, wherein said HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA): 100

267. The method according to claim 250, wherein said HDAC inhibitor is pyroxamide, represented by the structure: 101

268. The method according to claim 250, wherein said HDAC inhibitor is represented by the structure: 102 wherein R₃ and R₄ are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R₃ and R₄ bond together to form a piperidine group; R₂ is a hydroxylamino group; and n is an integer from 5 to 8.

269. The method according to claim 250, wherein said HDAC inhibitor is represented by the structure: 103 wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from 4 to 8.

270. The method according to claim 250, wherein said HDAC inhibitor is represented by the structure: 104 wherein A is an amide moiety, R₁ and R₂ are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R₄ is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. application Ser. No. 10/379,149, filed on Mar. 4, 2003, which claims the benefit of U.S. Provisional Application No. 60/361,759, filed Mar. 4, 2002. The entire teachings of these applications are incorporated herein by reference.

GOVERNMENT INTEREST STATEMENT

[0002] This invention was made in whole or in part with government support under grant number 1R21 CA 096228-01 awarded by the National Cancer Institute. The government may have certain rights in the invention.

FIELD OF THE INVENTION

[0003] The present invention describes methods of treating cutaneous T-cell lymphomas (CTCL), peripheral T-cell lymphomas (PTCL) and head and neck cancers. The present invention provides methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylases (HDAC) administration of pharmaceutical compositions comprising HDAC inhibitors. The oral formulations of the pharmaceutical compositions have favorable pharmacokinetic profiles such as high bioavailability and surprisingly give rise to high blood levels of the active compounds over an extended period of time.

BACKGROUND OF THE INVENTION

[0004] Throughout this application various publications are referenced by arabic numerals within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0005] Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms that normally govern proliferation and differentiation. For many years there have been two principal strategies for chemotherapeutic treatment of cancer: a) blocking hormone-dependent tumor cell proliferation by interference with the production or peripheral action of sex hormones; and b) killing cancer cells directly by exposing them to cytotoxic substances, which injure both neoplastic and normal cell populations.

[0006] Cancer therapy is also being attempted by the induction of terminal differentiation of the neoplastic cells (1). In cell culture models differentiation has been reported by exposure of cells to a variety of stimuli, including: cyclic AMP and retinoic acid (2,3), aclarubicin and other anthracyclines (4).

[0007] Despite many advances in the field of oncology, the majority of solid tumors remain incurable in the advanced stages. Cytotoxic therapy is used in most cases, however, it often causes significant morbidity to the patient without significant clinical benefit. Less toxic and more specific agents to treat and control advanced malignancies are being explored.

[0008] There is abundant evidence that neoplastic transformation does not necessarily destroy the potential of cancer cells to differentiate (1,5,6). There are many examples of tumor cells which do not respond to the normal regulators of proliferation and appear to be blocked in the expression of their differentiation program, and yet can be induced to differentiate and cease replicating. A variety of agents, including some relatively simple polar compounds (5,7-9), derivatives of vitamin D and retinoic acid (10-12), steroid hormones (13), growth factors (6,14), proteases (15,16), tumor promoters (17,18), and inhibitors of DNA or RNA synthesis (4,19-24), can induce various transformed cell lines and primary human tumor explants to express more differentiated characteristics.

[0009] Early studies identified a series of polar compounds that were effective inducers of differentiation in a number of transformed cell lines (8,9). Of these, the most effective inducer was the hybrid polar/apolar compound N,N′-hexamethylene bisacetamide (HMBA) (9). The use of this polar/apolar compound to induce murine erythroleukemia cells (MELC) to undergo erythroid differentiation with suppression of oncogenicity has proved a useful model to study inducer-mediated differentiation of transformed cells (5,7-9). HMBA-induced MELC terminal erythroid differentiation is a multi-step process. Upon addition of HMBA to MELC (745A-DS19) in culture, there is a latent period of 10 to 12 hours before commitment to terminal differentiation is detected. Commitment is defined as the capacity of cells to express terminal differentiation despite removal of inducer (25). Upon continued exposure to HMBA there is progressive recruitment of cells to differentiate. The present inventors have reported that MELC cell lines made resistant to relatively low levels of vincristine become markedly more sensitive to the inducing action of HMBA and can be induced to differentiate with little or no latent period (26).

[0010] HMBA is capable of inducing phenotypic changes consistent with differentiation in a broad variety of cells lines (5). The characteristics of the drug-induced effect have been most extensively studied in the murine erythroleukemia cell system (MELC) (5,25,27,28). MELC induction of differentiation is both time and concentration dependent. The minimum concentration required to demonstrate an effect in vitro in most strains is 2 to 3 mM; the minimum duration of continuous exposure generally required to induce differentiation in a substantial portion (>20%) of the population without continuing drug exposure is about 36 hours.

[0011] The primary target of action of HMBA is not known. There is evidence that protein kinase C is involved in the pathway of inducer-mediated differentiation (29). The in vitro studies provided a basis for evaluating the potential of HMBA as a cytodifferentiation agent in the treatment of human cancers (30). Several phase I clinical trials with HMBA have been completed (31-36). Clinical trials have shown that this compound can induce a therapeutic response in patients with cancer (35,36). However, these phase I clinical trials also have demonstrated that the potential efficacy of HMBA is limited, in part, by dose-related toxicity which prevents achieving optimal blood levels and by the need for intravenous administration of large quantities of the agent, over prolonged periods.

[0012] It has been reported that a number of compounds related to HMBA with polar groups separated by apolar linkages that, on a molar basis, are as active (37) or 100 times more active than HMBA (38). As a class, however, it has been found that the symmetrical dimers such as HMBA and related compounds are not the best cytodifferentiating agents.

[0013] It has unexpectedly been found that the best compounds comprise two polar end groups separated by a flexible chain of methylene groups, wherein one or both of the polar end groups is a large hydrophobic group. Preferably, the polar end groups are different and only one is a large hydrophobic group. These compounds are unexpectedly a thousand times more active than HMBA and ten times more active than HMBA related compounds.

[0014] Histone deacetylase inhibitors such as suberoylanilide hydroxamide acid (SAHA), belong to this class of agents that have the ability to induce tumor cell growth arrest, differentiation and/or apoptosis (39). These compounds are targeted towards mechanisms inherent to the ability of a neoplastic cell to become malignant, as they do not appear to have toxicity in doses effective for inhibition of tumor growth in animals (40). There are several lines of evidence that histone acetylation and deacetylation are mechanisms by which transcriptional regulation in a cell is achieved (41). These effects are thought to occur through changes in the structure of chromatin by altering the affinity of histone proteins for coiled DNA in the nucleosome. There are five types of histones that have been identified in nucleosomes (designated H1, H2A, H2B, H3 and H4). Each nucleosome contains two of each histone type within its core, except for H1, which is present singly in the outer portion of the nucleosome structure. It is believed that when the histone proteins are hypoacetylated, there is a greater affinity of the histone to the DNA phosphate backbone This affinity causes DNA to be tightly bound to the histone and renders the DNA inaccessible to transcriptional regulatory elements and machinery. The regulation of acetylated states occurs through the balance of activity between two enzyme complexes, histone acetyl transferase (HAT) and histone deacetylase (HDAC). The hypoacetylated state is thought to inhibit transcription of associated DNA. This hypoacetylated state is catalyzed by large multiprotein complexes that include HDAC enzymes. In particular, HDACs have been shown to catalyze the removal of acetyl groups from the chromatin core histones.

[0015] The inhibition of HDAC by SAHA is thought occur through direct interaction with the catalytic site of the enzyme as demonstrated by X-ray crystallography studies (42). The result of HDAC inhibition is not believed to have a generalized effect on the genome, but rather, only affects a small subset of the genome (43). Evidence provided by DNA microarrays using malignant cell lines cultured with a HDAC inhibitor shows that there are a finite (1-2%) number of genes whose products are altered. For example, cells treated in culture with HDAC inhibitors show a consistent induction of the cyclin-dependent kinase inhibitor p21 (44). This protein plays an important role in cell cycle arrest. HDAC inhibitors are thought to increase the rate of transcription of p21 by propagating the hyperacetylated state of histones in the region of the p21 gene, thereby making the gene accessible to transcriptional machinery. Genes whose expression is not affected by HDAC inhibitors do not display changes in the acetylation of regional associated histones (45).

[0016] It has been shown in several instances that the disruption of HAT or HDAC activity is implicated in the development of a malignant phenotype. For instance, in acute promyelocytic leukemia, the oncoprotein produced by the fusion of PML and RAR alpha appears to suppress specific gene transcription through the recruitment of HDACs (46). In this manner, the neoplastic cell is unable to complete differentiation and leads to excess proliferation of the leukemic cell line.

[0017] Cutaneous T-cell lymphomas and peripheral T-cell lymphomas are forms of non-Hodgkin's lymphoma. Cutaneous T-cell lymphomas are a group of lymphoproliferative disorders characterized by localization of malignant T lymphocytes to the skin at presentation. CTCL frequently involves the skin, bloodstream, regional lymph nodes and spleen. Mycosis fungoides (MF), the most common and indolent form of CTCL, is characterized by patches, plaques or tumors containing epidermotropic CD4 ⁺ CD45RO ⁺ helper/memory T cells. MF may evolve into a leukemic variant, Sezary syndrome (SS), or transform to large cell lymphoma. The condition causes severe skin itching, pain and edema. Currently, CTCL is treated topically with steroids, photochemotherapy and chemotherapy, as well as radiotherapy. Peripheral T-cell lymphomas originate from mature or peripheral (not central or thymic) T-cell lymphocytes as a clonal proliferation from a single T-cell and are usually either predominantly nodal or extranodal tumors. They have T-cell lymphocyte cell-surface markers and clonal arrangements of the T-cell receptor genes. Approximately 16,000 to 20,000 people in the U.S. are affected by either CTCL or PTCL. These diseases are highly symptomatic. Patches, plaques and tumors are the clinical names of the different presentations. Patches are usually flat, possibly scaly and look like a “rash.” Mycosis fungoides patches are often mistaken for eczema, psoriasis or non-specific dermatitis until a proper diagnosis of mycosis fungoides is made. Plaques are thicker, raised lesions. Tumors are raised “bumps” which may or may not ulcerate. A common characteristic is itching or pruritis, although many patients do not experience itching. It is possible to have one or all three of these phases. For most patients, existing treatments are palliative but not curative.

[0018] According to the National Cancer Institute, head and neck cancers account for three percent of all cancers in the U.S. Most head and neck cancers originate in the squamous cells lining the structures found in the head and neck, and are often referred to as squamous cell carcinomas of the head and neck (SCCHN). Some head and neck cancers originate in other types of cells, such as glandular cells. Head and neck cancers that originate in glandular cells are called adenocarcinomas. Head and neck cancers are further defined by the area in which they begin, such as the oral cavity, nasal cavity, larynx, pharynx, salivary glands and lymph nodes of the upper part of the neck. It is estimated that 38,000 people in the U.S. developed head and neck cancer 2002. Approximately 60% of patients present with locally advanced disease. Only 30% of these patients achieve long-term remission after treatment with surgery and/or radiation. For patients with recurrent and/or metastatic disease, the median survival is approximately six months.

[0019] U.S. Pat. Nos. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and 6,511,990, issued to some of the present inventors, disclose compounds useful for selectively inducing terminal differentiation of neoplastic cells, which compounds have two polar end groups separated by a flexible chain of methylene groups or a by a rigid phenyl group, wherein one or both of the polar end groups is a large hydrophobic group. Some of the compounds have an additional large hydrophobic group at the same end of the molecule as the first hydrophobic group which further increases differentiation activity about 100 fold in an enzymatic assay and about 50 fold in a cell differentiation assay. Methods of synthesizing the compounds used in the methods and pharmaceutical compositions of this invention are fully described the aforementioned patents, the entire contents of which are incorporated herein by reference.

[0020] The aforementioned patents do not disclose specific oral formulations of the HDAC inhibitors or specific dosages and dosing schedules of the recited compounds. Importantly, the aforementioned patents do not disclose oral formulations that have favorable pharmacokinetic profiles such as high bioavailability which gives rise to high blood levels of the active compounds over an extended period of time.

[0021] The class of compounds of the present invention may be useful for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells and therefore aid in treatment of tumors in patients. Thus there is an urgent need to discover suitable dosages and dosing schedules of these compounds, and to develop formulations, preferably oral formulations, which give rise to steady, therapeutically effective blood levels of the active compounds over an extended period of time.

SUMMARY OF THE INVENTION

[0022] The present invention provides a method of treating cutaneous T-cell lymphomas (CTCL), peripheral T-cell lymphomas (PTCL) or head and neck cancers by administering an effective amount of an HDAC inhibitor, such as suberoylanilide hydroxamic acid (SAHA). SAHA can be administered in a total daily dose of up to 800 mg, preferably orally, once, twice or three times daily, continuously (every day) or intermittently (e.g., 3-5 days a week).

[0023] Oral SAHA has been safely administered in phase I and phase II clinical studies to patients suffering from in cutaneous T-cell lymphomas, peripheral T-cell lymphomas or head and neck cancers.

[0024] Furthermore, the present invention provides a method of treating cutaneous T-cell lymphomas, peripheral T-cell lymphomas or head and neck cancers by administering an effective amount of an HDAC inhibitor as described herein. The HDAC inhibitors can be administered in a total daily dose of up to 800 mg, preferably orally, once, twice or three times daily, continuously (i.e., every day) or intermittently (e.g., 3-5 days a week).

[0025] The present invention also provides methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells, as well as methods of treating cancer and of chemoprevention in subjects in need thereof, by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent. An effective amount of an HDAC inhibitor in the present invention can be up to a total daily dose of 800 mg.

[0026] The present invention further provides a safe, daily dosing regimen of the formulation of pharmaceutical compositions comprising an HDAC inhibitor which are easy to follow and to adhere to. These pharmaceutical compositions are suitable for oral administration and comprise a compound useful for treating cancer, chemoprevention, selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or which is a potent inhibitor of histone deacetylase (HDAC). The pharmaceutical compositions are further comprised of microcrystalline cellulose, croscarmellose sodium and magnesium stearate.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

[0028] FIG. 1 is a picture of a Western blot (top panel) showing the quantities of acetylated histone-4 (α-AcH4) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA. IV SAHA was administered at 200 mg infused over two hours. Oral SAHA was administered in a single capsule at 200 mg. The amount of α-AcH4 is shown at the indicated time points. Bottom panel: Coomassie blue stain.

[0029] FIG. 2 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-4 (α-AcH4) in the blood plasma of patients having a solid tumor, following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administered as in FIG. 1 . The amount of α-AcH4 is shown at the indicated time points. The experiment is shown in duplicate ( FIG. 2 A and FIG. 2B ). Bottom panels: Coomassie blue stain.

[0030] FIG. 3 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-4 (α-AcH4) ( FIG. 3A ) and acetylated histone-3 (α-AcH3) (FIGS. 3 B-E) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA, on Day 1 and Day 21. IV and Oral SAHA were administered as in FIG. 1 . The amount of α-AcH4 or α-AcH3 is shown at the indicated time points. Bottom panels: Coomassie blue stain.

[0031] FIG. 4 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 (α-AcH3) in the blood plasma of patients having a solid tumor, following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administered as in FIG. 1 . The amount of α-AcH3 is shown at the indicated time points. Bottom panel: Coomassie blue stain.

[0032] FIG. 5 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 (α-AcH3) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA. IV SAHA was administered at 400 mg infused over two hours. Oral SAHA was administered in a single capsule at 400 mg. The amount of α-AcH4 is shown at the indicated time points. The experiment is shown in triplicate ( FIGS. 5A and B ). Bottom panels: Coomassie blue stain.

[0033] FIG. 6 is a picture of a Western blot (top panel) showing the quantities of acetylated histone-3 (α-AcH3) in the blood plasma of patients having a solid tumor, following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administered as in FIG. 5 . The amount of α-AcH3 is shown at the indicated time points. Bottom panel: Coomassie blue stain.

[0034] FIG. 7 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 (α-AcH3) in the blood plasma of patients having a solid tumor following an oral or intravenous (IV) dose of SAHA, on Day 1 and Day 21. IV and Oral SAHA were administered as in FIG. 4 . The amount of α-AcH4 or α-AcH3 is shown at the indicated time points. The experiment is shown in triplicate (FIGS. 7 A-C). Bottom panels: Coomassie blue stain.

[0035] FIG. 8 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 (α-AcH3) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administer