Treatment of DNA damage related disorders

Abstract

The present invention provides methods and compositions for prophylaxis and treatment of a variety of disorders including DNA damage related disorders, cancer, ischemia, oxidative stress, atherosclerosis, and stroke using a chloroquine compound.

1 . A method of prophylaxis of cancer comprising administering to a subject at risk of cancer, an effective amount of a chloroquine compound, provided the subject has been free of a localized skin epithelialoma or carcinoma for at least a year before commencing administration of the chloroquine compound.  
     
     
         2 . The method of  claim 1 , wherein the subject has never suffered from a localized skin epithelialoma or carcinoma basal cell before commencing administration of the chloroquine compound.  
     
     
         3 . The method of  claim 1 , wherein the subject has never suffered from skin cancer.  
     
     
         4 . The method of  claim 1 , wherein the subject has been free of malaria for at least one year before commencing administration of the chloroquine compound.  
     
     
         5 . The method of  claim 1 , wherein the subject has never suffered from malaria before commencing administration of the chloroquine compound.  
     
     
         6 . The method of  claim 1 , wherein the subject is free of detectable antibodies against Epstein Barr virus.  
     
     
         7 . The method of  claim 1 , further comprising monitoring the subject for development of a cancer after administration of the chloroquine compound.  
     
     
         8 . The method of  claim 7 , wherein the monitoring comprising monitoring the subject for a cancer other than a localized skin epithelialoma or carcinoma basal cell.  
     
     
         9 . The method of  claim 7 , wherein the monitoring comprising taking a sample of a body fluid, or performing a scan of an internal organ.  
     
     
         10 . The method of  claim 1 , wherein the subject is at risk of cancer by having a precancerous tissue.  
     
     
         11 . The method of  claim 1 , wherein the subject has a first cancer, and is at risk of a second cancer.  
     
     
         12 . The method of  claim 1 , wherein the subject has a cancer and is undergoing radiation therapy to treat the cancer, the radiation therapy putting the subject at risk of a second cancer; and wherein the administration effects prophylaxis of the second cancer.  
     
     
         13 . The method of  claim 1 , wherein the chloroquine compound is administered before or during the radiation therapy.  
     
     
         14 . The method of  claim 1 , wherein the subject has a cancer and is undergoing chemotherapy to treat the cancer, the chemotherapy placing the subject at risk of a second cancer, and wherein the administration effects prophylaxis of the second cancer.  
     
     
         15 . The method of  claim 14 , wherein the chloroquine compound is administered before or during the chemotherapy.  
     
     
         16 . The method of  claim 1 , wherein the subject is at risk of cancer due to a genetic variation associated with increased risk of cancer.  
     
     
         17 . The method of  claim 1 , wherein the subject is at risk of cancer due to viral infection.  
     
     
         18 . The method of  claim 1 , wherein the subject is at risk of caner due to exposure to a carcinogen or irradiation.  
     
     
         19 . The method of  claim 1 , wherein the subject is at risk of cancer due to exposure to X-rays.  
     
     
         20 . The method of  claim 1 , further comprising determining presence of a genetic variation in an ATM gene of the subject associated with cancer.  
     
     
         21 . The method of  claim 1 , further comprising administering a chemopreventive agent other than the chloroquine compound to the subject.  
     
     
         22 . The method of  claim 1 , further comprising determining the risk of cancer in the subject before administering the chloroquine compound.  
     
     
         23 . The method of  claim 1 , wherein the chloroquine compound is administered intravenously.  
     
     
         24 . The method of  claim 1 , wherein the chloroquine compound is administered orally.  
     
     
         25 . The method of  claim 1 , wherein the subject is free of diseases of the immune system, infectious diseases, multiple-drug resistance, and neurological diseases.  
     
     
         26 . The method of  claim 1 , wherein the subject is free of psoriasis, malaria, protozoal infections, Epstein Barr virus infection, Alzheimer's disease, Parkinson's disease, lupus erythematosus, rheumatism, hypercalcemia, multiple sclerosis, and migraine.  
     
     
         27 . The method of  claim 1 , wherein the prophylaxis is effective to prevent detectable development of cancer for at least six months after administering the effective dosage.  
     
     
         28 . The method of  claim 1 , wherein the administering is performed before exposure of the subject to the risk of cancer.  
     
     
         29 . The method of  claim 1 , wherein the administering is performed at regular intervals for a period of at least six months.  
     
     
         30 . The method of claims  1 , wherein the chloroquine compound is selected from the group consisting of chloroquine, chloroquine phosphate, hydroxychloroquine, chloroquine diphosphate, chloroquine sulphate, hydroxychloroquine sulphate, or enantiomers, derivatives, analogs, metabolites, pharmaceutically acceptable salts, and mixtures thereof.  
     
     
         31 . The method of  claim 30 , wherein the compound is chloroquine, chloroquine phosphate or chloroquine diphosphate.  
     
     
         32 . The method of  claim 1 , wherein chloroquine compound has a systemic effect.  
     
     
         33 . The method of  claim 1 , wherein the patient is human and the dosage is 0.05 to 1 mg/kg per day.  
     
     
         34 . The method of  claim 1 , wherein the patient is human and the dosage is 0.2 to 0.6 mg/kg per day.  
     
     
         35 . The method of  claim 34 , wherein the patient has been exposed to a carcinogen or radiation, and the dosage is administered at least on the day of exposure and the day following exposure.  
     
     
         36 . The method of  claim 34 , wherein the patient has been exposed to a carcinogen or radiation, and the dosage is administered at least on the day before the exposure, on the day of the exposure, and at least on the day following the exposure.  
     
     
         37 . The method of  claim 1 , wherein the patient is human and has genetic susceptible to cancer, and the dosage is 0.2 to 0.6 mg/kg week.  
     
     
         38 . The method of claims  1 , wherein the amount of the compound administered is up to about 10 mg/kg/day.  
     
     
         39 . The method of claims  1 , wherein the amount of the compound administered is more than about 0.1 mg/kg/day.  
     
     
         40 . The method of  claim 1 , wherein the amount of the compound administered is more than about 1.0 mg/kg/day.  
     
     
         41 . The method of  claim 1 , wherein the amount of the compound administered is less than about 50 mg/kg/day.  
     
     
         42 . The method of  claim 1 , wherein the amount of the compound administered is less than about 10 mg/kg/day.  
     
     
         43 . The method of  claim 1 , wherein the chloroquine compound is administered more than once a week.  
     
     
         44 . The method  claim 1 , wherein the chloroquine compound is administered daily.  
     
     
         45 . The method of  claim 1 , wherein the chloroquine compound is formulated in a sustained release formulation.  
     
     
         46 . The method of  claim 1 , wherein the subject is human.  
     
     
         47 . A method of therapeutically treating cancer comprising administering to a subject having a cancer, an effective amount of a chloroquine compound whereby the cancer is therapeutically treated.  
     
     
         48 . The method of  claim 47 , wherein the cancer is other than a localized skin epithelialoma or carcinoma basal cell.  
     
     
         49 . The method of  claim 47 , wherein the cancer is other than skin cancer.  
     
     
         50 . The method of  claim 47 , wherein the treatment reduces or eliminates further growth of the cancer.  
     
     
         51 . The method of  claim 47 , wherein the treatment shrinks or eliminates the tumor.  
     
     
         52 . The method of  claim 47 , wherein the treatment inhibits invasion of the cancer into tissues of the subject and/or inhibits metastasis of the cancer.  
     
     
         53 . The method of  claim 47 , further comprising monitoring changes in the cancer responsive to the administering.  
     
     
         54 . The method of  claim 53 , wherein the monitoring comprising taking a sample of a body fluid, or performing a scan of an internal organ.  
     
     
         55 . The method of  claim 47 , further comprising identifying a genetic variation in an ATM gene of the subject associated with cancer.  
     
     
         56 . The method of  claim 47 , further comprising administering a chemotherapeutic agent other than the chloroquine compound to the subject.  
     
     
         57 . The method of  claim 47 , further comprising determining presence of the cancer before the administering step.  
     
     
         58 . The method of  claim 47 , wherein the subject is free of diseases of the immune system, infectious diseases, multiple drug resistance and neurological diseases.  
     
     
         59 . The method of  claim 47 , wherein the patient is human and the dosage is 0.05 to 1 mg/kg per week.  
     
     
         60 . The method of  claim 1 , wherein the patient is human and the dosage is 0.2 to 0.6 mg/kg per day.  
     
     
         61 . The method of  claim 47 , wherein the subject is free of psoriasis, malaria, protozoal infections, Alzheimer's disease, Parkinson's disease, lupus erythematosus, rheumatism, hypercalcemia, multiple sclerosis, and migraine.