Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders

Abstract

Treatment of hyperproliferative disorders (including tumors and psoriasis) by pulse administration of a drug (such as Vitamin D or an analog) that increases blood or tissue levels of Vitamin D. The drug is administered at a sufficient dose to have an anti-proliferative effect, but the pulsed administration of the drug avoids the development of severe symptomatic or life-threatening hypercalcemia. In particular embodiments, avoidance of hypercalcemia (as measured by serum levels of calcium above normal range) is avoided altogether. In a particular example, the drug is calcitriol administered at an oral dose of about 0.5 mcg/kg once a week.

We claim:  
     
         1 . A method for the treatment of a hyperproliferative disease in a subject, wherein the hyperproliferative disease responds to treatment with a Vitamin D drug, comprising administering to the subject a therapeutically effective pulse dose of the Vitamin D drug in a sufficient amount to have an antiproliferative effect, without inducing severe symptomatic hypercalcemia.  
     
     
         2 . The method of  claim 1 , comprising administering the Vitamin D drug to a subject having a neoplasm that expresses a Vitamin D receptor.  
     
     
         3 . The method of  claim 2 , wherein the neoplasm is selected from the group of cancer of the prostate, breast, colon, lung, head and neck, pancreas, endometrium, bladder, cervix, ovaries, squamous cell carcinoma, renal cell carcinoma, myeloid and lymphocytic leukemia, lymphoma, medullary thryoid carcinoma, melanoma, multiple myeloma, retinoblastoma, and sarcomas of the soft tissues and bone.  
     
     
         4 . The method of  claim 3 , wherein the neoplasm is breast cancer or prostate cancer.  
     
     
         5 . The method of  claim 1 , wherein the Vitamin D drug has a calcemic index greater than or equal to calcipitriol.  
     
     
         6 . The method of  claim 1 , wherein the Vitamin D drug has a calcemic index greater than 1.0.  
     
     
         7 . The method of  claim 5 , wherein the Vitamin D drug has a half-life that is no greater than about 1 day.  
     
     
         8 . The method of  claim 7 , wherein the Vitamin D drug has a half-life that is no greater than about 6 hours.  
     
     
         9 . The method of  claim 8 , wherein the Vitamin D drug is administered in an amount that raises a serum level of Vitamin D in the subject with a tumor to a supraphysiologic amount for a sufficient period of time to induce differentiation or regression of the tumor without causing symptomatic hypercalcemia.  
     
     
         10 . The method of  claim 1 , wherein the Vitamin D drug is calcitriol, which is administered in a therapeutically effective pulse dose no more than once every three days.  
     
     
         11 . The method of  claim 10 , wherein the calcitriol is administered orally in a dose of at least 0.12 mcg/kg per day no more than once per week.  
     
     
         12 . The method of  claim 10 , wherein the calcitriol is administered orally in a dose of at least 0.48 mcg/kg or about 1 mcg/kg per day no more than once per week.  
     
     
         13 . A method of treating a tumor in a subject, wherein the tumor expresses a Vitamin D receptor and is responsive to treatment with a Vitamin D drug, the method comprising administering orally to the subject, no more than once every three days, a dose of calcitriol of about 0.5 mcg/kg.  
     
     
         14 . The method of  claim 13 , wherein the Vitamin D drug is administered to the subject no more than once per week.  
     
     
         15 . A composition comprising a Vitamin D drug in a pharmaceutical dosage form in a dosage that would cause hypercalcemia is administered daily.  
     
     
         16 . The composition of  claim 15 , wherein the Vitamin D drug is calcitriol, contained in the composition in an amount of at least 5 mcg.  
     
     
         17 . The composition of  claim 16 , wherein the pharmaceutical dosage form is an oral dosage form containing at least 100 mcg per unit of the oral dosage form.  
     
     
         18 . The composition of  claim 16 , wherein the pharmaceutical dosage form is a tablet or capsule.  
     
     
         19 . The composition of  claim 16 , wherein the Vitamin D drug is calcitriol, and the pharmaceutical dosage form is a tablet containing at least 5 mcg calcitriol.  
     
     
         20 . The method of  claim 1 , wherein the subject is prescribed a reduced calcium diet for a sufficient period of time prior to administration of the Vitamin D drug to reduce absorption of dietary calcium.  
     
     
         21 . A method of treating in a subject a tumor that expresses a Vitamin D receptor, the method comprising raising a blood level of Vitamin D to a sufficiently supraphysiologic level for a sufficient period of time to inhibit growth of the tumor, without inducing hypercalcemia in the subject.  
     
     
         22 . The method of  claim 21 , wherein the blood level of Vitamin D is raised by administering a Vitamin D drug to the subject.  
     
     
         23 . The method of  claim 22 , wherein the Vitamin D drug is calcitriol.  
     
     
         24 . The method of  claim 23 , wherein the calcitriol is administered in a dose of about 0.50 mcg/kg once per week.