Dramatic simplification of a method to treat neoplastic disease by radiation

Abstract

A method of treating tumors with radiation is disclosed, wherein the tumor is sensitized by administering a tumor sensitizing agent comprising 5-chloro-2′-deoxycytidine, 4-N-methyl FdC and a cytidine deaminase inhibitor to a patient having the tumor. The tumor is then subjected to radiation.

1 . A method of treating tumors in a subject in need of such treatment, comprising the following steps: 
 (A) administering a tumor-treating effective amount of an agent to the subject, wherein the agent comprises 
 (a) 5-chloro-2′-deoxycytidine without a cytidine deaminase inhibitor, 5-fluoro-2′-deoxycytidine (FdC), 5-fluoro-2′-deoxyuridine (FdU), and N-(phosphonacetyl)-L-aspartate (PALA), wherein 5-chloro-2′-deoxycytidine enhances the incorporation of a radiosensitizing metabolite of 5-chloro-2′-deoxycytidine into DNA, precluding the need for administering an inhibitor for the formation of TTP,  
 (b) 5-chloro-2′-deoxycytidine and a cytidine deaminase inhibitor, without 5-fluoro-2′-deoxycytidine (FdC), 5-fluoro-2′-deoxyuridine (FdU), and N-(phosphonacetyl)-L-aspartate (PALA), wherein 5-chloro-2′-deoxycytidine enhances the incorporation of a radiosensitizing metabolite of 5-chloro-2′-deoxycytidine into DNA, precluding the need for administering an inhibitor for the formation of TTP,  
 (c) 5-chloro-2′-deoxycytidine and 4-N-methylamino FdC, or  
 (d) 5-chloro-2′-deoxycytidine, 4-N-methylamino FdC and a cytidine deaminase inhibitor; and  
   (B) exposing the subject to a tumor-treating effective amount of radiation.    
     
     
         2 . The method of  claim 1 , wherein said agent is administered in a slow release formulation.  
     
     
         3 . The method of  claim 1 , wherein the cytidine deaminase inhibitor is tetrahydrouridine, deoxytetrahydrouridine, a pyrimidin-2-one nucleoside, a F pyrimidin-2-one nucleoside, a diazepin-2-1-nucleoside, 1-(2-Deoxy-2-fluoro-β-D arabinofuranosyl)-1,2-dihydropyrimidin-2-one, 2′-Deoxy-2′-F-arazebularine, diazoepinone, 4-hydromethyl-2-oxopyrimidin-2-one nucleoside, or 2′-fluoro-2′-deoxyarabinosyl-tetrahydrouracil.  
     
     
         4 . The method of  claim 3 , wherein said pyrimidin-2-one nucleoside is 1-β-ribofuranocyl-1,2-dihydropyrimidin-2-one (Zebularine) or 5-fluoro-pyrimidin-2-one-nucleoside.  
     
     
         5 . The method of  claim 4 , wherein the cytidine deaminase inhibitor is tetrahydrouridine or Zebularine.  
     
     
         6 . The method of  claim 5 , wherein the cytidine deaminase inhibitor is tetrahydrouridine.  
     
     
         7 . The method of  claim 1 , wherein said subject is a human.  
     
     
         8 . The method of  claim 1 , wherein the radiation is selected from the group consisting of radiation from protons as a radiation source, radiation from a radiation source implanted proximal to the tumor, radiation from a radionuclide attached to monoclonal antibodies, radiation in a gamma knife, 3D conformal radiation, and radiation in steriotactic radiosurgery.  
     
     
         9 . The method of  claim 8 , wherein said radiation source implanted proximal to the tumor comprises yttrium 90 needles or iridium needles.  
     
     
         10 . The method of  claim 8 , wherein said radionuclide is yttrium 90.  
     
     
         11 . The method of  claim 1 , further comprising administering bisulfite to the subject before exposing the subject to radiation.  
     
     
         12 . The method of  claim 11 , further comprising administering cysteine to the subject before exposing the subject to radiation.  
     
     
         13 . The method of  claim 1 , further comprising exposing the subject to radiation before step (A).  
     
     
         14 . A method of hypomethylating genes in a subject in need of such hypomethylation, comprising administering a gene-hypomethylating effective amount of an agent to the subject, wherein said agent comprises 
 (a) 5-chloro-2′-deoxycytidine without a cytidine deaminase inhibitor,    (b) 5-chloro-2′-deoxycytidine and a cytidine deaminase inhibitor,    (c) 5-chloro-2′-deoxycytidine and 4-N-methylamino FdC, or    (d) 5-chloro-2′-deoxycytidine, 4-N-methylamino FdC and a cytidine deaminase inhibitor.    
     
     
         15 . The method of  claim 14 , wherein the cytidine deaminase inhibitor is tetrahydrouridine, deoxytetrahydrouridine, a pyrimidin-2-one nucleoside, a F pyrimidin-2-one nucleoside, a diazepin-2-1-nucleoside, 1-(2-Deoxy-2-fluoro-β-D arabinofuranosyl)-1,2-dihydropyrimidin-2-one, 2′-Deoxy-2′-F-arazebularine, diazoepinone, 4-hydromethyl-2-oxopyrimidin-2-one nucleoside, or 2′-fluoro-2′-deoxyarabinosyl-tetrahydrouracil.  
     
     
         16 . The method of  claim 15 , wherein said pyrimidin-2-one nucleoside is 1-β-riboduranocyl-1,2-dihydropyrimidin-2-one (Zebularine) or 5-fluoro-pyrimidin-2-one-nucleoside.  
     
     
         17 . The method of  claim 16 , wherein the cytidine deaminase inhibitor is tetrahydrouridine or Zebularine.  
     
     
         18 . The method of  claim 17 , wherein the cytidine deaminase inhibitor is tetrahydrouridine.  
     
     
         19 . The method of  claim 14 , wherein said subject is a human.  
     
     
         20 . The method of  claim 14 , further comprising exposing the subject to a tumor-treating effective amount of radiation, wherein the agent hypomethylates genes silenced in a tumor to reduce (A) the aggressiveness of the tumor, (B) the metastatic propensity of the tumor, (C) the genetic instability of the tumor, and/or (D) the resistance of the tumor to drug or radiation treatment.  
     
     
         21 . A pharmaceutical composition comprising 5-chloro-2′-deoxycytidine and 4-N-methylamino FdC.