Sensitization to another anticancer therapy and/or amelioration of a side effect of another anitcancer therapy by treatment with a GST-activated anticancer compound

Abstract

A method of sensitizing a mammal, especially a human, to another anticancer therapy by administering a sensitizing effective amount of a GST-activated anticancer compound. A method of ameliorating a side effect of another anticancer therapy in a mammal, especially a human, by administering an ameliorating effective amount of a GST-activated anticancer compound. Pharmaceutical compositions for the methods. The GST-activated anticancer compound is preferably a compound of U.S. Pat. No. 5,556,942, and more preferably canfosfamide, especially as the hydrochloride salt.

1 . A method of sensitizing a mammal to another anticancer therapy comprising administering a sensitizing effective amount of a GST-activated anticancer compound.  
   
   
       2 . The method of  claim 1  where the mammal is a human.  
   
   
       3 . The method of  claim 2  where the GST-activated anticancer compound is a compound of the formula  
     
       
         
         
             
             
         
       
     
     or an amide, ester, or salt thereof, where: 
 L is a cytotoxic electron withdrawing leaving group;  
 S x  is —S(═O)—, —S(═O) 2 —, —S(═NH)—, —S(═O)(═NH)—, —S + (C 1 -C 6  alkyl)—, —Se(═O)—, —Se(═O) 2 —, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;  
 each of R 1 , R 2  and R 3  is independently H or a non-interfering substituent;  
 n is 0, 1 or 2;  
 Y is selected from the group consisting of  
                     
 where m is 1 or 2; and  
 AA c  is an amino acid linked through a peptide bond to the remainder of the compound.  
 
   
   
       4 . The method of  claim 3  where the GST-activated anticancer compound is canfosfamide or a salt thereof.  
   
   
       5 . The method of  claim 4  where the GST-activated anticancer compound is canfosfamide hydrochloride.  
   
   
       6 . The method of  claim 1  where the another anticancer therapy is selected from one or more of chemotherapy, molecular targeted therapy, biologic therapy, and radiotherapy.  
   
   
       7 . The method of  claim 6  where the another anticancer therapy is administration of one or more of an alkylating agent, an antimetabolite, a natural product, a hormone or hormone antagonist, a miscellaneous agent, a functional therapeutic agent, a gene therapy agent, an antisense therapy agent, a tyrosine kinase inhibitor, a gene expression modulator, a phenotype-directed therapy agent, a monoclonal antibody, an immunotoxin, a radioimmunoconjugate, a cancer vaccine, an interferon, and an interleukin.  
   
   
       8 . The method of  claim 7  where the another anticancer therapy is administration of one or more of busulfan, thiotepa, chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, uramustine, carmustine, lomustine, streptozocin, dacarbazine, procarbazine, temozolamide, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, methotrexate, permetrexed, raltitrexed, trimetrexate, cladribine, chlorodeoxyadenosine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine, azacitidine, capecitabine, cytarabine, edatrexate, floxuridine, fluorouracil, gemcitabine, troxacitabine, bleomycin, dactinomycin, mithramycin, mitomycin, mitoxantrone, porfiromycin, daunorubicin, daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, valrubicin, L-asparaginase, PEG-L-asparaginase, paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, irinotecan, topotecan, amsacrine, etoposide, teniposide, fluoxymesterone, testolactone, bicalutamide, cyproterone, flutamide, nilutamide, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, dexamethasone, prednisone, diethylstilbestrol, fulvestrant, raloxifene, tamoxifen, toremifine, buserelin, goserelin, leuprolide, triptorelin, medroxyprogesterone acetate, megestrol acetate, levothyroxine, liothyronine, altretamine, arsenic trioxide, gallium nitrate, hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, lenalidomide, methoxsalen, sodium porfimer, bortezomib, erlotinib hydrochloride, gefitinib, imatinib mesylate, semaxanib, adapalene, bexarotene, trans-retinoic acid, 9-cis-retinoic acid, and N-(4-hydroxyphenyl)retinamide, alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, trastuzumab, gemtuzumab ozogamicin,  131 I-tositumomab, interferon-α 2a , interferon-α 2b , aldesleukin, denileukin diftitox, and oprelvekin.  
   
   
       9 . The method of  claim 8  where the another anticancer therapy is administration of: a platinum compound, optionally in further combination with gemcitabine or a taxane; gemcitabine; a taxane; an anthracycline; oxaliplatin, optionally in further combination with capecitabine or fluorouracil/leucovorin; and gemcitabine or a platinum compound, in further combination with a vinca alkaloid.  
   
   
       10 . The method of  claim 9  where the another anticancer therapy is administration of cisplatin or carboplatin.  
   
   
       11 . The method of  claim 10  where the another anticancer therapy is administration of cisplatin or carboplatin as sole therapy.  
   
   
       12 . The method of  claim 6  where the another anticancer therapy is administration of two or more of chemotherapy, molecular targeted therapy, biologic therapy; or radiotherapy.  
   
   
       13 . The method of  claim 6  where the another anticancer therapy is administration of two or more chemotherapy agents.  
   
   
       14 . The method of  claim 6  where the another anticancer therapy includes radiation therapy.  
   
   
       15 . The method of  claim 14  where the another anticancer therapy is radiation therapy.  
   
   
       16 . The method of  claim 1  where the dosing of the GST-activated anticancer compound is about 5-50%, especially about 10-50%, of the usual therapeutic dose of that GST-activated anticancer compound, at 1-35 day intervals.  
   
   
       17 . The method of  claim 16  where the dosing is at 1-5 week intervals, especially at 1, 2, 3, or 4 week intervals.  
   
   
       18 . The method of  claim 16  where the GST-activated anticancer compound is canfosfamide hydrochloride and the dosing is about 125-450 mg/m 2  at 1-5 week intervals, especially at 1, 2, 3, or 4 week intervals.  
   
   
       19 . A method of ameliorating a side effect of another anticancer therapy in a mammal comprising administering an ameliorating effective amount of a GST-activated anticancer compound.  
   
   
       20 . The method of  claim 19  where the mammal is a human.  
   
   
       21 . The method of  claim 20  where the GST-activated anticancer compound is a compound of the formula  
     
       
         
         
             
             
         
       
     
     or an amide, ester, or salt thereof, where: 
 L is a cytotoxic electron withdrawing leaving group;  
 S x  —S(═O)—, —S(═O) 2 —, —S(═NH)—, —S(═O)(═NH)—, —S + (C 1 -C 6  alkyl)—, —Se(═O)—, —Se(═O) 2 —, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;  
 each of R 1 , R 2  and R 3  is independently H or a non-interfering substituent;  
 n is 0, 1 or 2;  
 Y is selected from the group consisting of  
                     
 where m is 1 or 2; and  
 AA c  is an amino acid linked through a peptide bond to the remainder of the compound.  
 
   
   
       22 . The method of  claim 21  where the GST-activated anticancer compound is canfosfamide or a salt thereof.  
   
   
       23 . The method of  claim 22  where the GST-activated anticancer compound is canfosfamide hydrochloride.  
   
   
       24 . The method of  claim 19  where the another anticancer therapy is selected from one or more of chemotherapy, molecular targeted therapy, biologic therapy, and radiotherapy.  
   
   
       25 . The method of  claim 24  where the another anticancer therapy is administration of one or more of an alkylating agent, an antimetabolite, a natural product, a hormone or hormone antagonist, a miscellaneous agent, a functional therapeutic agent, a gene therapy agent, an antisense therapy agent, a tyrosine kinase inhibitor, a gene expression modulator, a phenotype-directed therapy agent, a monoclonal antibody, an immunotoxin, a radioimmunoconjugate, a cancer vaccine, an interferon, and an interleukin.  
   
   
       26 . The method of  claim 25  where the another anticancer therapy is administration of one or more of busulfan, thiotepa, chlorambucil, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, uramustine, carmustine, lomustine, streptozocin, dacarbazine, procarbazine, temozolamide, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, methotrexate, permetrexed, raltitrexed, trimetrexate, cladribine, chlorodeoxyadenosine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine, azacitidine, capecitabine, cytarabine, edatrexate, floxuridine, fluorouracil, gemcitabine, troxacitabine, bleomycin, dactinomycin, mithramycin, mitomycin, mitoxantrone, porfiromycin, daunorubicin, daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, valrubicin, L-asparaginase, PEG-L-asparaginase, paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, irinotecan, topotecan, amsacrine, etoposide, teniposide, fluoxymesterone, testolactone, bicalutamide, cyproterone, flutamide, nilutamide, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, dexamethasone, prednisone, diethylstilbestrol, fulvestrant, raloxifene, tamoxifen, toremifine, buserelin, goserelin, leuprolide, triptorelin, medroxyprogesterone acetate, megestrol acetate, levothyroxine, liothyronine, altretamine, arsenic trioxide, gallium nitrate, hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, lenalidomide, methoxsalen, sodium porfimer, bortezomib, erlotinib hydrochloride, gefitinib, imatinib mesylate, semaxanib, adapalene, bexarotene, trans-retinoic acid, 9-cis-retinoic acid, and N-(4-hydroxyphenyl)retinamide, alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, trastuzumab, gemtuzumab ozogamicin,  131 I-tositumomab, interferon-α 2a , interferon-α 2b , aldesleukin, denileukin diftitox, and oprelvekin.  
   
   
       27 . The method of  claim 26  where the another anticancer therapy is administration of: a platinum compound, optionally in further combination with gemcitabine or a taxane; gemcitabine; a taxane; an anthracycline; oxaliplatin, optionally in further combination with capecitabine or fluorouracil/leucovorin; and gemcitabine or a platinum compound, in further combination with a vinca alkaloid.  
   
   
       28 . The method of  claim 27  where the another anticancer therapy is administration of cisplatin or carboplatin.  
   
   
       29 . The method of  claim 28  where the another anticancer therapy is administration of cisplatin or carboplatin as sole therapy.  
   
   
       30 . The method of  claim 24  where the another anticancer therapy is administration of two or more of chemotherapy; molecular targeted therapy; biologic therapy; and radiotherapy.  
   
   
       31 . The method of  claim 24  where the another anticancer therapy is administration of two or more chemotherapy agents.  
   
   
       32 . The method of  claim 24  where the another anticancer therapy includes radiation therapy.  
   
   
       33 . The method of  claim 32  where the another anticancer therapy is radiation therapy.  
   
   
       34 . The method of  claim 19  where the dosing of the GST-activated anticancer compound is about 5-50%, especially about 10-50%, of the usual therapeutic dose of that GST-activated anticancer compound, at 1-35 day intervals.  
   
   
       35 . The method of  claim 34  where the dosing is at 1-5 week intervals, especially at 1, 2, 3, or 4 week intervals.  
   
   
       36 . The method of  claim 34  where the GST-activated anticancer compound is canfosfamide hydrochloride and the dosing is about 125-450 mg/m 2  at 1-5 week intervals, especially at 1, 2, 3, or 4 week intervals.  
   
   
       37 . A pharmaceutical composition for sensitizing a mammal, especially a human, to another anticancer therapy, comprising a sensitizing effective amount of a GST-activated anticancer compound and an excipient.  
   
   
       38 . The composition of  claim 37  where the GST-activated anticancer compound is a compound of the formula  
     
       
         
         
             
             
         
       
     
     or an amide, ester, or salt thereof, where: 
 L is a cytotoxic electron withdrawing leaving group;  
 S x  is —S(═O)—, —S(═O) 2 —, —S(═NH)—, —S(═O)(═NH)—, —S + (C 1 -C 6  alkyl)—, —Se(═O)—, —Se(═O) 2 —, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;  
 each of R 1 , R 2  and R 3  is independently H or a non-interfering substituent;  
 n is 0, 1 or 2;  
 Y is selected from the group consisting of  
                     
 where m is 1 or 2; and  
 AA c  is an amino acid linked through a peptide bond to the remainder of the compound.  
 
   
   
       39 . The composition of  claim 38  where the GST-activated anticancer compound is canfosfamide or a salt thereof.  
   
   
       40 . The composition of  claim 39  where the GST-activated anticancer compound is canfosfamide hydrochloride.  
   
   
       41 . A pharmaceutical composition for ameliorating a side effect of another anticancer therapy in a mammal, especially a human, comprising an ameliorating effective amount of a GST-activated anticancer compound and an excipient.  
   
   
       42 . The composition of  claim 41  where the GST-activated anticancer compound is a compound of the formula  
     
       
         
         
             
             
         
       
     
     or an amide, ester, or salt thereof, where: 
 L is a cytotoxic electron withdrawing leaving group;  
 S x  is —S(═O)—, —S(═O) 2 —, —S(═NH)—, —S(═O)(═NH)—, —S + (C 1 -C 6  alkyl)—, —Se(═O)—, —Se(═O) 2 —, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;  
 each of R 1 , R 2  and R 3  is independently H or a non-interfering substituent;  
 n is 0, 1 or 2;  
 Y is selected from the group consisting of  
                     
 where m is 1 or 2; and  
 AA c  is an amino acid linked through a peptide bond to the remainder of the compound.  
 
   
   
       43 . The composition of  claim 42  where the GST-activated anticancer compound is canfosfamide or a salt thereof.  
   
   
       44 . The composition of  claim 43  where the GST-activated anticancer compound is canfosfamide hydrochloride.