Use of substituted hexitols including dianhydrogalactitol and analogs to treat neoplastic disease and cancer stem cells including glioblastoma multiforme and medulloblastoma

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of glioblastoma multiforme and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism.

1 . A method of treating glioblastoma multiforme that has O 6 -methylguanine-DNA methyltransferase (MGMT)-driven drug resistance, comprising the step of administering a therapeutically effective quantity of dianhydrogalactitol to a patient suffering from glioblastoma multiforme that has O 6 -methylguanine-DNA methyltransferase (MGMT)-driven drug resistance. 
     
     
         2 . The method of  claim 1 , wherein the glioblastoma multiforme is characterized by an MGMT gene having a methylated promoter. 
     
     
         3 . The method of  claim 1 , wherein the glioblastoma multiforme is glioblastoma multiforme resistant to temozolomide. 
     
     
         4 . The method of  claim 1 , wherein the therapeutically effective quantity of dianhydrogalactitol is a dosage of from about 1 mg/m 2  to about 40 mg/m 2 . 
     
     
         5 . The method of  claim 1 , wherein the therapeutically effective quantity of dianhydrogalactitol is a quantity of dianhydrogalactitol that results in a concentration of dianhydrogalactitol in the cerebrospinal fluid (CSF) of equal to or greater than 5 mM. 
     
     
         6 . The method of  claim 1 , wherein dianhydrogalactitol is administered by a route selected from the group consisting of intravenous and oral administration. 
     
     
         7 . The method of  claim 1 , wherein the therapeutically effective quantity of dianhydrogalactitol is a quantity that results in a cytotoxic concentration of the substituted hexitol derivative in the cerebrospinal fluid CSF. 
     
     
         8 . A method of treating glioblastoma multiforme resistant to temozolomide comprising the step of administering a therapeutically effective quantity of dianhydrogalactitol to a patient suffering from glioblastoma multiforme resistant to temozolomide. 
     
     
         9 . The method of  claim 8 , wherein the therapeutically effective quantity of dianhydrogalactitol is a dosage of from about 1 mg/m 2  to about 40 mg/m 2 . 
     
     
         10 . The method of  claim 8 , wherein the therapeutically effective quantity of dianhydrogalactitol is a quantity of dianhydrogalactitol that results in a concentration of dianhydrogalactitol in the cerebrospinal fluid (CSF) of equal to or greater than 5 mM. 
     
     
         11 . The method of  claim 8 , wherein dianhydrogalactitol is administered by a route selected from the group consisting of intravenous and oral administration. 
     
     
         12 . The method of  claim 8  further comprising the step of administering a therapeutically effective dose of ionizing radiation.