Methods of treating neurofibromatosis with perillyl alcohol

1. A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of perillyl alcohol, an iso-perillyl alcohol, or a combination thereof.

2. A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of a carbamate of perillyl alcohol, a carbamate of an iso-perillyl alcohol, or a combination thereof, wherein the carbamate of perillyl alcohol is perillyl alcohol conjugated with temozolomide, rolipram or dimethyl celecoxib, and wherein the carbamate of an iso-perillyl alcohol is an iso-perillyl alcohol conjugated with temozolomide, rolipram or dimethyl celecoxib.

3. The method of claim 2 , wherein the carbamate of perillyl alcohol is 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester.

4. The method of claim 2 , wherein the carbamate of perillyl alcohol is 3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl-carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester.

5. The method of claim 1 or 2 , further comprising administering temozolomide, dimethyl celecoxib, or rolipram to the subject.

6. The method of claim 1 or 2 , further comprising administering to the subject a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

7. The method of claim 1 or 2 , further comprising administering prostratin to the subject.

8. The method of claim 1 or 2 , wherein the administration is by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.

9. A method of inhibiting or decreasing Ras level and/or activity in a cell or in a subject, comprising administering to the cell or the subject a carbamate of perillyl alcohol, a carbamate of an iso-perillyl alcohol, or a combination thereof, wherein the carbamate of perillyl alcohol is perillyl alcohol conjugated with temozolomide, rolipram or dimethyl celecoxib, and wherein the carbamate of an iso-perillyl alcohol is an iso-perillyl alcohol conjugated with temozolomide, rolipram or dimethyl celecoxib.

10. The method of claim 9 , wherein the carbamate of perillyl alcohol is 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester.

11. The method of claim 9 , wherein the perillyl alcohol carbamate is 3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl-carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester.

12. The method of claim 9 , further comprising administering temozolomide, dimethyl celecoxib, or rolipram.

13. The method of claim 9 , further comprising administering a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

14. The method of claim 9 , further comprising administering prostratin.

15. The method of claim 9 , wherein said administration is by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.

16. A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of perillyl alcohol.

17. The method of claim 16 , further comprising administering rolipram to the subject.

18. The method of claim 16 , further comprising administering a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

19. The method of claim 18 , wherein the statin is lovastatin.

20. The method of claim 16 , further comprising administering prostratin to the subject.

21. A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of iso-perillyl alcohol.

22. The method of claim 21 , further comprising administering rolipram to the subject.

23. The method of claim 21 , further comprising administering a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

24. The method of claim 23 , wherein the statin is lovastatin.

25. The method of claim 2 , wherein the carbamate of perillyl alcohol is 4-bis-N,N′-4-isopropenyl cyclohex-1-enylmethyloxy carbonyl [5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl] benzenesulfonamide.

26. The method of claim 9 , wherein the carbamate of perillyl alcohol is 4-bis-N,N′-4-isopropenyl cyclohex-1-enylmethyloxy carbonyl [5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl] benzenesulfonamide.

27. The method of claim 2 , wherein the carbamate of an iso-perillyl alcohol is (3-Methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic acid-4-isopropylidene cyclohex-1-enylmethyl ester, 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropylidene cyclohex-1-enylmethyl ester, or 4-(Bis-N,N′-4-isopropylidene cyclohex-1-enylmethyloxy carbonyl [5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl] benzenesulfonamide.

28. The method of claim 9 , wherein the carbamate of an iso-perillyl alcohol is (3-Methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic acid-4-isopropylidene cyclohex-1-enylmethyl ester, 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropylidene cyclohex-1-enylmethyl ester, or 4-(Bis-N,N′-4-isopropylidene cyclohex-1-enylmethyloxy carbonyl [5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl] benzenesulfonamide.