Methods of treating cancer using compositions comprising perillyl alcohol derivative

Abstract

A method for treating brain metastases of a cancer in a mammal includes administering to the mammal a therapeutically effective amount of a perillyl alcohol carbamate, such as TMZ-POH. The brain metastases can be originated or spread from breast cancer. The penllyl alcohol derivative may be perillyl alcohol conjugated with a therapeutic agent, such as a chemotherapeutic agent. The chemotherapeutic agents that may be used in the present invention include a DNA alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enzyme inhibitor, and a receptor antagonist.

1 . A method for treating a brain metastasis of a cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound comprising perillyl alcohol (POH) conjugated with temozolomide (TMZ). 
     
     
         2 . The method of  claim 1 , wherein the compound is 3-methyl 4-oxo-3,4-dihydroimidazo [5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic acid-4-isopropenyl cyclohex-l-enylmethyl ester (TMZ-POH). 
     
     
         3 . The method of  claim 1 , wherein the brain metastasis originates from a primary cancer selected from the group consisting of a systemic cancer, lung cancer, prostate cancer, breast cancer, hematopoietic cancer, ovarian cancer, bladder cancer, germ cell tumors, kidney cancer, leukemia, lymphoma, and melanoma. 
     
     
         4 . The method of  claim 3 , wherein the brain metastasis originates from breast cancer. 
     
     
         5 . The method of  claim 1 , wherein the compound is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly. 
     
     
         6 . The method of  claim 1 , wherein the administering comprises administering the compound intranasally using a nasal delivery device selected from the group consisting of an intranasal inhaler, an intranasal spray device, an atomizer, a nebulizer, a metered dose inhaler (MDI), a pressurized dose inhaler, an insufflator, a unit dose container, a pump, a dropper, a nasal spray bottle, a squeeze bottle and a bi-directional device. 
     
     
         7 . The method of  claim 1 , further comprising treating the mammal with radiation before, during, or after the administration of the compound. 
     
     
         8 . The method of  claim 1 , further comprising delivering to the mammal an additional chemotherapeutic agent. 
     
     
         9 . A method for treating metastatic breast cancer in a mammal that has spread to the brain of the mammal, comprising administering to the mammal a therapeutically effective amount of 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 (TMZ-POH).