Modulation of signal transduction

Abstract

A polypeptide is identified as being functionally included in a signal transduction pathway having a biological effect. Contemplated polypeptides are different from a retinoic acid receptor, a retinoid X receptor, or a cellular retinoic acid binding protein, however bind a retinoid or retinoid metabolite, and binding of the retinoid or retinoid metabolite lead to a modulation of the biological effect. In particularly contemplated methods, a retinoid or retinoid metabolite is administered to a cell or mammal in a concentration effective to modulate the biological effect.

1 . A method of treatment of a drug-resistant tumor to deter the proliferation thereof, which method comprises administering a xenobiotic antiproliferative agent to a human inflicted with said tumor in combination with an effective amount of at least one of the following three retinoids: 9-cis-retinoic acid (9-cis-RA); 4-hydroxyphenyl-retinamide; and 4-(retinonyl)-benzyloxyglucuronate, which amount is effective to bind to xenobiotic transport protein of the ATP binding cassette family and thereby deter transport of said xenobiotic agent out of the tumor cells. 
   
   
       2 . The method of  claim 1  wherein said combination of xenobiotic agent and retinoid is carried out by injection to the tumor being targeted. 
   
   
       3 . The method of  claim 2  wherein said xenobiotic agent and said retinoid are injected in an amount between about 3 mg and about 20 mg per kilogram of body weight of the human. 
   
   
       4 . The method of  claim 1  wherein the xenobiotic agent and an effective amount of 9-cis-retinoic acid are administered. 
   
   
       5 . The method of  claim 1  wherein the xenobiotic agent and an effective amount of 4-hydroxyphenyl-retinamide are administered. 
   
   
       6 . The method of  claim 1  wherein the xenobiotic agent and an effective amount of 4-(retinonyl)-benzyloxyglucuronate are administered. 
   
   
       7 . The method of  claim 1  when the xenobiotic antiproliferative agent is an agent which causes programmed cell death. 
   
   
       8 . A method of treatment of a human to limit neuroedegenerative demyelinating disease, which method comprises administering an effective amount of at least one of the following three retinoids: 9-cis-retinoic acid (9-cis-RA); 4-hydroxyphenyl-retinamide; and 4-(retinonyl)-benzyloxyglucuronate, which administration targets connexin proteins in myelinated fibers to deter demyelinization and thereby mitigate neurodegeneration. 
   
   
       9 . The method according to  claim 8  wherein said administration is effected either orally or parenterally to limit Charcot-Marie-Tooth disease and protect against apparent symptoms of Charcot-Marie-Tooth disease in mild cases. 
   
   
       10 . The method according to  claim 9  wherein an amount of said retinoid between about 3 mg and 20 mg per kilogram of body weight of the human is administered systemically or locally. 
   
   
       11 . The method according to  claim 10  wherein 9-cis-retinoic acid (9-cis-RA) is administered locally. 
   
   
       12 . A method of treatment which affects metabolism in a human in order to combat obesity, which method comprises administering an effective amount of at least one of at least one of the following three retinoids: 9-cis-retinoic acid (9-cis-RA); 4-hydroxyphenyl-retinamide; and 4-(retinonyl)-benzyloxyglucuronate, which retinoids are effective to interact with mitochondrial uncoupler proteins and affect metabolism through UCP isoforms and thereby counteract obesity by deterring weight gain. 
   
   
       13 . The method according to  claim 12  wherein administration is effected either orally or parenterally. 
   
   
       14 . The method according to  claim 13  wherein an amount of said retinoid between about 3 mg and 20 mg per kilogram of body weight of the human is administered.