Compositions and methods to control abnormal cell growth

Abstract

A class of compounds commonly containing a trialkylammonium group have been synthesized and characterized as anticancer compounds. A representative of this class, N,N-diethyl-N-methyl-2-[(9-oxo-9H-thioxanthen-2-yl)methoxy]ethanaminium iodide (CCDTHT) was shown in various tumor models to decrease tumor volume, enhance the effects of other chemotherapeutic agents including cisplatin, reduce chemotherapy-induced loss of body weight, and increase survival of animals co-treated with toxic amounts of cisplatin. CCDTHT had even greater effects on tumor volume, body weight, and survival when administered to animals together with the human protein placental alkaline phosphatase. These trialkylammonium group-containing compounds and alkaline phosphatases, particularly in combination with each other and other therapies, may be used to treat cancer and other cell proliferative diseases.

1 . A composition administered to a patient with cancer at therapeutically effective doses to reduce tumor size in order to prevent tumor-induced or treatment-induced patient weight loss, which increases patient survival, wherein the composition comprises alkaline phosphatase or a physiologically active derivative thereof wherein the derivative is selected from fragments of alkaline phosphatase that demonstrate efficiencies similar or more effective than native alkaline phosphatase, a suitable carrier, and a heterocyclic compound having one or two quaternary ammonium groups represented by the formula: 
     
       
         
         
             
             
         
       
       wherein R 1  and R 3-8  are independently hydrogen, C 1 -C 26  straight, branched or cyclic alkanes or alkenes, aromatic hydrocarbons, alcohols, ethers, aldehydes, ketones, carboxylic acids, amines, amides, nitriles, or five- and/or six-membered heterocyclic moieties; 
       wherein R 9  and R 10  considered together are ═O or ═CH-L-N + (R 11 , R 12 , R 13 ) or 
       wherein R 9  and R 10  considered independently are —OH or -L-N + (R 11 , R 12 , R 13 ); 
       wherein R 2  is hydrogen, —CH 3 , —X—L-N+(R 11 , R 12 , R 13 )Z − ; or 
       -L-N + (R 11 , R 12 , R 13 )Z − ; 
       wherein V is —S − , —Se − , —C − , —O −  or —N; 
       wherein Y is —S − , —Se − , —C − , —O −  or —N; 
       wherein —X is —CH 2   − , —OCH 2   − , —CH2O − , SCH2 −  or —CH 2 S − ; 
       wherein L is a C 1 -C 4  straight alkane, alkene, thiol, ether, or amine; 
       wherein R 11 , R 12  and R 13  are independently C 1 -C 4  straight alkanes, alkenes, thiols, amines, ethers or alcohols; and 
       wherein Z −  is Cl − , Br −  or I − . 
     
   
   
       2 . The composition of  claim 1  wherein R 11 , R 12 , and R 13  are independently methyl, ethyl, propyl, allyl, ether, sulfhydryl, amino, or hydroxyl groups. 
   
   
       3 . The composition of  claim 1  wherein the heterocyclic compound is a thioxanthone and R 2  is -X-L-N + (R 11 , R 12 , R 13 )Z − . 
   
   
       4 . The composition of  claim 1  wherein the heterocyclic compound is [3-(3,4-dimethyl-9-oxo-9H-thioxanthen-2-yloxy)-2-hydroxypropyl] trimethylammonium chloride. 
   
   
       5 . The composition of  claim 1  wherein the heterocyclic compound is N,N,-diethyl-N-methyl-2-[9-oxo-9H-thioxanthen-2-yl)methoxy] ethanaminium iodide. 
   
   
       6 . The composition of  claim 1  wherein the heterocyclic compound is a thioxanthene and wherein R 2  hydrogen or CH 3 , R 9  and R 10  considered together are ═CH-L-N + (R 11 , R 12 , R 13 ); L is —(CH 2 ) 2 — or —(CH 2 ) 3 —; and R 1  and R 3-8  are hydrogen. 
   
   
       7 . The composition of  claim 6  wherein the heterocyclic compound is N,N-diethyl-N-allyl-3-(2-methyl-9H-thioxanthen-9-ylidene)-propane-1-aminium bromide. 
   
   
       8 . The composition of  claim 6  wherein the heterocyclic compound is N,N,N-trimethyl-3-(2-methyl-9H-thioxanthen-9-ylidene)-propane-1-aminium iodide. 
   
   
       9 . The composition of  claim 6  wherein the heterocyclic compound is N,N,N-trimethyl-3-(9H-thioxanthen-9-ylidene)-propane-1-aminium iodide. 
   
   
       10 . The composition of  claim 1 , wherein the R 11 , R 12 , or R 13  in the heterocyclic trialkylammonium compound is modified by a targeting moiety comprising antibody, folic acid, steroid, fatty acid or a peptide developed to bind to a specific cell surface protein or cross the cell membrane. 
   
   
       11 . The composition of  claim 1  wherein the alkaline phosphatase is obtained from mammalian tissue. 
   
   
       12 . The composition of  claim 11  wherein the alkaline phosphatase is placental alkaline phosphatase, intestinal alkaline phosphatase, tissue non-specific alkaline phosphatase or placental alkaline phosphatase-like germ-cell type alkaline phosphatase. 
   
   
       13 . The composition of  claim 11  wherein the alkaline phosphatase is a human alkaline phosphatase. 
   
   
       14 . The composition of  claim 1  wherein the alkaline phosphatase is produced by a recombinant method with a corresponding coding gene sequence being transferred into and expressed in a single cell or multi cell organism. 
   
   
       15 . The composition of  claim 1  wherein the composition is administered by an oral, topical, intravenous, intraarterial, subcutaneous, intraperitoneal, intradermal, intratissue, intramuscular, intraportal, intracranial, infusion, or aerosol delivery route, or by a minipump. 
   
   
       16 . The composition of  claim 1  wherein the alkaline phosphatase and heterocyclic compound are administered in a suitable carrier simultaneously. 
   
   
       17 . The composition of  claim 1  wherein the alkaline phosphatase and heterocyclic trialkylammonium compound components are administered in a suitable carrier separately once daily, or once, twice, or three times a week. 
   
   
       18 . The composition of  claim 1  wherein the alkaline phosphatase and heterocyclic trialkylammonium compound components are administered in a suitable carrier simultaneously or separately via different administration routes. 
   
   
       19 . The composition of  claim 1  wherein a suitable carrier is 0.9% sodium chloride and the administration is via an injection method. 
   
   
       20 . The composition of  claim 1  wherein the composition suitable carrier is a vaseline-based material and administration is via a topical administration method. 
   
   
       21 . The composition of  claim 1  wherein the composition is a tablet, gel capsule, or a liquid composed of one or more ingredients conforming to industrial standards, and administrated orally.