Methods and compositions for optimizing blood and tissue stability of camptothecin and other albumin-binding therapeutic compounds

Abstract

The present invention provides methods and formulations for optimizing the anti-cancer and anti-HIV activities of a camptothecin drug, including camptothecin and its related analogs including 9-aminocamptothecin and 9-nitrocamptothecin. The invention involves methodologies and formulations that limit human serum albumin-mediated reduction of the anti-cancer and anti-HIV effects of the camptothecins, and the methods and formulations provide combination therapies in which binding of the camptothecin agent to human serum albumin can be modulated by the administration of a competing agent such as ibuprofen, clofibrate or clofibric acid that also binds human serum albumin. Reduced camptothecin drug binding to human serum albumin can result in elevated camptothecin free drug levels and thus improve the effectiveness of treatment regimens involving these drugs. Further agents such as methotrexate and AZT can also be used in cancer and HIV-positive patients employing camptothecin drugs.

1 . A method for increasing the free drug levels of a camptothecin drug that binds human serum albumin (HSA) during anti-topoisomerase I-based therapy in humans, said method comprising administering, to a human or animal patient in need of said therapy, at least one HSA-binding compound so as to block the camptothecin binding site on HSA and thus reduce the binding of the camptothecin drug to HSA in human blood or plasma so that the free drug levels of the camptothecin drug will be increased and so that greater levels of the camptothecin will reach the drug target at the treatment site, wherein the HSA-binding compound is administered separately from the camptothecin drug. 
     
     
         2 . The method according to  claim 1 , wherein the HSA-binding compound is selected from the group consisting: of long chain fatty acids (C 16 -C 20 ; including oleic, palmitic, linoleic, stearic, arachidonic, and palmitoleic); medium chain fatty acids (C 6 -C 14 ; including caprylate or octanoate); phospholipids (lysolecithins, oleoyllysophosphatidic acid, phosphatidylcholine, phosphatidylethanolamine); eicosanoid derivatives (Leukotrienes, thromboxanes, prostaglandins A, E, F, and I); steroid hormones (cholesterol, testosterone, pregnenolone, cortisol, androsterone, indol, progesterone, estrogen); vitamin D (both monohydroxyvitamin D and dihydroxyvitamin D); bile salts (lithocholate, chenodeoxycholate, deoxycholate, ursodeoxycholate, cholate, glycolitocholate, glycochenodeoxycholate, taurochenodoxycholate, glycodeoxycholate, glycocholate, taurocholate); bilirubins (bilirubin, biliverdin, xanthobilirubin, EZ-cyclobilirubin, δ-bilirubin); porphyrins (hematin, protoporphyrin); warfarin; salicylates, ibuprofen; prednisone; iophenoxate; sulfisoxazole; phenylbutazone; oxphenylbutazone; digitoxin; indomethacin; tolbutamide; furosemide; phenyloin; chlorpropamide; chlorthiazide; the penicillins (including oxacillin, benzylpenicillin); acetotrizoate; isulfobromophthalein; deacetylcolchicine; dansylamide; dansylglutamine; dansylsarcosine; indomethacin; phenylpropazone; azobenzene derivatives; sulfobromophthalein; triiodobenzoate; benzodiazepine (including diazepam); flufenamate; iopanoate; ethacrynate; panproxen; clofibrate; L-tryptophan; N-acetyl-L-tryptophan; 6-methyltryptophan; thyroxine; 3,5,3′-L-triiodothyronine; indole propionate; kynurenine; ethacrynate; panproxen; chlorophenoxyisobutyrate; 3′azido-3′-deoxythymidine; non-steroidal anti-inflammatory agents containing ionized carboxyl groups; gossypol; meso-2,3-dimercaptosuccinic acid; captopril; N-2-mercaptoethyl-1,2-diaminopropane; disulfuramacetaminophen, dis-dichlorodiamineplatinum 9II; pyridoxal 5′-phosphate; aquocobalamin form of vitamin B12; folate; ascorbate (and its oxidation product dehydroascorbate); melatonin; α-melanotropin; gastrin; corticotropin and methotrexate, the camptothecins (both α-hydroxy-δ-lactone congeners and β-hydroxy-δ-lactone congeners), and combinations of the above. 
     
     
         3 . The method according to  claim 1 , wherein the HSA-binding compound is ibuprofen. 
     
     
         4 . The method according to  claim 1 , wherein the HSA-binding compound is selected from the group consisting of clofibrate and clofibric acid. 
     
     
         5 . The method according to  claim 1 , wherein the HSA-binding compound is administered intravenously or orally. 
     
     
         6 . The method according to  claim 1 , wherein the binding of the HSA-binding compound to HSA results in the displacement of the camptothecin drug from its HSA binding site. 
     
     
         7 . The method according to  claim 1  wherein the camptothecin drug is selected from the group consisting of camptothecins that contain either an E-ring α-hydroxy lactone pharmacophore or an E-ring β-hydroxy lactone pharmacophore, homocamptothecins, homosilatecans, 9-aminocamptothecin, 10-hydroxycamptothecin, 10,11-methylenedioxycamptothecin, 9-nitro-10,11-methylenedioxycamptothecin, 9-chloro-10,11-methylenedioxycamptothecin, 9-amino-10,11-methylenedioxycamptothe-cin, 9-nitrocamptothecin, topotecan, and combinations of the above. 
     
     
         8 . A method for increasing the free drug levels of a camptothecin drug that binds human serum albumin (HSA) during anti-topoisomerase I-based therapy in humans, said method comprising administering, to a human or animal patient in need of said therapy, at least one HSA-binding compound selected from the group consisting of clofibrate and clofibric acid so as to block the camptothecin binding site on HSA and thus reduce the binding of the camptothecin drug to HSA in human blood or plasma so that the free drug levels of the camptothecin drug will be increased and so that greater levels of the camptothecin will reach the drug target at the treatment site, wherein the HSA-binding compound is administered separately from the camptothecin drug. 
     
     
         9 . The method according to  claim 8 , wherein the HSA-binding compound is administered intravenously or orally. 
     
     
         10 . A method for improving the free lactone levels of at least one camptothecin drug that binds in the carboxylate form to HSA during anti-topoisomerase I-based therapy, said method comprising administering, to a human or animal patient in need of said therapy, at least one HSA-binding compound selected from the group consisting of clofibrate and clofibric acid so as to block the camptothecin binding site on HSA and thus reduce the binding of the camptothecin drug to HSA in human blood or plasma so that the free lactone levels of the camptothecin drug will be increased in human blood or plasma and so that greater levels of the camptothecin will reach the drug target at the treatment site, wherein the HSA-binding compound is administered separately from the camptothecin drug. 
     
     
         11 . The method according to  claim 10 , wherein the HSA-binding compound is administered intravenously or orally. 
     
     
         12 . The method according to  claim 10 , wherein the binding of the HSA-binding compound to HSA occurs by covalent or non-covalent means. 
     
     
         13 . The method according to  claim 10 , wherein the binding of the HSA-binding agent to HSA results in the displacement of the camptothecin drug from its HSA binding site. 
     
     
         14 . A method for enhancing the cellular uptake and cellular concentration of the camptothecin drug that binds to HSA during anti-topoisomerase I-based therapy, said method comprising administering, to a human or animal patient receiving said therapy, at least one HSA-binding compound, wherein the compound is selected from the group consisting of clofibrate and clofibric acid, so as to block the camptothecin binding site on HSA and thus reduce the binding of the camptothecin drug to HSA in human blood or plasma so that the cellular uptake and cellular concentration of the camptothecin drug will be enhanced in human blood or plasma and so that greater levels of the camptothecin drug will reach the drug target at the treatment site, wherein the HSA-binding compound is administered separately from the camptothecin drug. 
     
     
         15 . The method according to  claim 14 , wherein the HSA-binding compound is administered intravenously or orally. 
     
     
         16 . A therapeutic composition, comprising an effective therapeutic amount of at least one camptothecin drug that binds HSA during anti-topoisomerase I-based therapy in humans and at least one HSA binding compound selected from the group consisting of clofibrate and clofibric acid. 
     
     
         17 . The composition of  claim 16 , further comprising one or more additional agents selected from the group consisting of antineoplastic agents and anthracyclines. 
     
     
         18 . A method for improving the effectiveness of a therapeutic treatment regimen using a camptothecin drug that binds to HSA during anti-topoisomerase I-based therapy comprising administering to a human or animal patient in need of said therapy a HSA-binding compound, wherein said HSA-binding compound is selected from the group consisting of clofibrate and clofibric acid, so as to block the camptothecin binding site on HSA and thus reduce the binding of the camptothecin drug to HSA in human blood or plasma so that the effectiveness of the therapeutic treatment regimen of the camptothecin drug will be improved and so that greater levels of the camptothecin will reach the drug target at the treatment site, wherein the HSA binding compound is administered separately from the camptothecin drug. 
     
     
         19 . The method according to  claim 18  wherein said therapeutic treatment regimen comprises therapeutic treatment for AIDS. 
     
     
         20 . The method according to  claim 18  wherein said therapeutic treatment regimen comprises therapeutic treatment for cancer.