Radiosensitizer Formulations and Methods for Use

Abstract

The present invention provides radiosensitizer compositions, in controlled-release formulations or other acceptable formulations, particularly nitrohistidine radiosensitizer compositions, which may be administered by any suitable means including oral, intravenous, arterial infusion, intraperitoneal, intramuscular, subcutaneous, surgical, and topical. Optionally, radiosensitizer compositions may be formulated with other agents, including chemotherapy agents and agents that provide a synergistic radiosensitizing effect. Methods of potentiating radiotherapy cancer treatment of cancers in humans, particularly of astrocytomas, are also presented, wherein a radiosensitizer composition is administered and radiotherapy is directed to the site of the tumor. Chemotherapy regimens may also be used as adjuvant therapy.

1 . A radiosensitizer composition comprising an effective amount of a compound of formula (I) or formula (II): 
     
       
         
         
             
             
         
       
     
     wherein R 1  is H or alkyl. 
   
   
       2 . The radiosensitizer composition according to  claim 1 , wherein the nitrohistidine is a non-racemic, substantially optically pure nitro-L-histidine. 
   
   
       3 . The radiosensitizer composition of  claim 1 , wherein the nitrohistidine is a compound of formula (I). 
   
   
       4 . The radiosensitizer composition of  claim 1 , wherein the nitrohistidine is a compound of formula (II). 
   
   
       5 . A radiosensitizer composition according to  claim 1 , further comprising one or more agents. 
   
   
       6 . A radiosensitizer composition according to  claim 5 , wherein the one or more agents is buthionine sulfoximine, (PALA) N-(phosphonylacetyl)-L-aspartic acid (PALA), a chemotherapeutic agent, or any combination thereof. 
   
   
       7 . A radiosensitizer composition according to  claim 5 , wherein the chemotherapeutic agent is a nitrosourea agent, cisplatin, carboplatin (CBDCA), bleomycin, doxorubicin, methotrexate, cyclophosphamide, gemcitabine, treosulfan, 5-fluorouracil, dacarbazine, temozolomide, 9-nitrocamptothecin, vincristine, fotemustine, lomustine, a cytokine, an interferon, or any combination thereof. 
   
   
       8 . A radiosensitizer composition according to  claim 1 , further comprising a biomodulator compound. 
   
   
       9 . The radiosensitizer composition according to  claim 8 , wherein the biomodulator compound is a slow-release compound. 
   
   
       10 . The radiosensitizer composition according to  claim 9 , wherein the slow-release compound is a biodegradable polymer. 
   
   
       11 . The radiosensitizer composition according to  claim 10 , wherein the biodegradable polymer is selected from the group consisting of a homopolymer of lactic acid; a homopolymer of glycolic acid; a copolymer of poly-D,L,-lactic acid and glycolic acid; a water-insoluble peptide salt of a luteinizing hormone-releasing hormone (LHRH) analogue; a poly(phosphoester); a bis(p-carboxyphenoxy)propane (CPP) with sebacic acid copolymer; a polyanhydrides polymer; poly(lactide)-co-glycolide)polyethylene glycol copolymers; and an ethylene-vinyl acetate copolymer. 
   
   
       12 . A radiosensitizer composition comprising an effective amount of a compound of formula (I) or (II): 
     
       
         
         
             
             
         
       
     
     wherein R 1  is H or alkyl; and a slow-release biodegradable polymer. 
   
   
       13 . The radiosensitizer composition according to  claim 12  wherein the nitrohistidine is a non-racemic, substantially optically pure nitro-L-histidine. 
   
   
       14 . The radiosensitizer composition of  claim 12 , wherein the nitrohistidine is a compound of formula (I). 
   
   
       15 . The radiosensitizer composition of  claim 12 , wherein the nitrohistidine is a compound of formula (II). 
   
   
       16 . A radiosensitizer composition according to  claim 12 , further comprising buthionine sulfoximine, a nitrosourea agent, N-(phosphonylacetyl)-L-aspartic acid (PALA), a chemotherapeutic agent, or any combination thereof. 
   
   
       17 . A radiosensitizer composition according to  claim 16 , wherein the chemotherapeutic agent is a nitrosourea agent, cis-platin, carboplatin (CBDCA), bleomycin, doxorubicin, methotrexate, cyclophosphamide, gemcitabine, treosulfan, 5-fluorouracil, dacarbazine, temozolomide, 9-nitrocamptothecin, vincristine, fotemustine, lomustine, a cytokine, an interferon, or any combination thereof. 
   
   
       18 . The radiosensitizer composition according to  claim 12 , wherein the biodegradable polymer is selected from the group consisting of a homopolymer of lactic acid; a homopolymer of glycolic acid; a copolymer of poly-D,L,-lactic acid and glycolic acid; a water-insoluble peptide salt of a luteinizing hormone-releasing hormone (LHRH) analogue; a poly(phosphoester); a bis(p-carboxyphenoxy)propane (CPP) with sebacic acid copolymer; a polyanhydrides polymer; poly(lactide)-co-glycolide)polyethylene glycol copolymers; and an ethylene-vinyl acetate copolymer. 
   
   
       19 . A method of potentiating radiotherapy cancer treatment comprising:
 administering to a patient in need thereof a therapeutically effective amount of a composition comprising a radiosensitizer of formula (I) or (II):   
     
       
         
         
             
             
         
       
     
     wherein R 1  is H or alkyl; and
 directing radiotherapy at a prescribed dosage to a locus of cancer. 
 
   
   
       20 . The radiosensitizer composition of  claim 19 , wherein the nitrohistidine is a compound of formula (I). 
   
   
       21 . The radiosensitizer composition of  claim 19 , wherein the nitrohistidine is a compound of formula (II). 
   
   
       22 . A method of potentiating radiotherapy cancer treatment according to  claim 19 , wherein the composition further comprises one or more agents. 
   
   
       23 . A method of potentiating radiotherapy cancer treatment according to  claim 22 , wherein the one or more agents is buthionine sulfoximine, a nitrosourea agent, N-(phosphonylacetyl)-L-aspartic acid (PALA), a chemotherapeutic agent, or any combination thereof. 
   
   
       24 . A method of potentiating radiotherapy cancer treatment according to  claim 23 , wherein the chemotherapeutic agent is a nitrosourea agent, cisplatin, carboplatin (CBDCA), bleomycin, doxorubicin, methotrexate, cyclophosphamide, gemcitabine, treosulfan, 5-fluorouracil, dacarbazine, temozolomide, 9-nitrocamptothecin, vincristine, fotemustine, lomustine, a cytokine, an interferon, or any combination thereof. 
   
   
       25 . A method of potentiating radiotherapy cancer treatment according to  claim 23 , further comprising:
 administering chemotherapy after directing radiotherapy.   
   
   
       26 . A method of potentiating radiotherapy cancer treatment according to  claim 25 , wherein administering chemotherapy includes administering a nitrosourea agent, cisplatin, carboplatin (CBDCA), bleomycin, doxorubicin, methotrexate, cyclophosphamide, gemcitabine, treosulfan, 5-fluorouracil, dacarbazine, temozolomide, 9-nitrocamptothecin, vincristine, fotemustine, lomustine, a cytokine, an interferon, or any combination thereof. 
   
   
       27 . A method of potentiating radiotherapy cancer treatment according to  claim 23 , further comprising:
 administering chemotherapy before directing radiotherapy.   
   
   
       28 . A method of potentiating radiotherapy cancer treatment according to  claim 27 , wherein administering chemotherapy includes administering a nitrosourea agent, cisplatin, carboplatin (CBDCA), bleomycin, doxorubicin, methotrexate, cyclophosphamide, gemcitabine, treosulfan, 5-fluorouracil, dacarbazine, temozolomide, 9-nitrocamptothecin, vincristine, fotemustine, lomustine, a cytokine, an interferon, or any combination thereof. 
   
   
       29 . A method of potentiating radiotherapy cancer treatment according to  claim 19 , further comprising, in administering, providing the composition in a slow-release formulation. 
   
   
       30 . A method of potentiating radiotherapy cancer treatment according to  claim 29 , further comprising administering the slow-release formulation by any suitable means including oral, intravenous, arterial infusion, intraperitoneal, intramuscular, subcutaneous, surgical, and topical. 
   
   
       31 . A method according to  claim 29 , wherein the slow-release formulation comprises a biodegradable polymer. 
   
   
       32 . A method according to  claim 31 , wherein the biodegradable polymer is selected from the group consisting of a homopolymer of lactic acid; a homopolymer of glycolic acid; a copolymer of poly-D,L,-lactic acid and glycolic acid; a water-insoluble peptide salt of a luteinizing hormone-releasing hormone (LHRH) analogue; a poly(phosphoester); a bis(p-carboxyphenoxy)propane (CPP) with sebacic acid copolymer; a polyanhydrides polymer; poly(lactide)-co-glycolide)polyethylene glycol copolymers; and an ethylene-vinyl acetate copolymer. 
   
   
       33 . A method according to  claim 29 , wherein the slow-release formulation releases the radiosensitizer over a period of four or more weeks. 
   
   
       34 . A method according to  claim 29 , wherein the slow-release formulation releases the radiosensitizer over a period of one week or more. 
   
   
       35 . A method according to  claim 29 , wherein the slow-release formulation releases the radiosensitizer over a period of 24 hours or more. 
   
   
       36 . A method according to  claim 29  wherein the cancer is any of a brain cancer, a lung cancer, a head-and-neck cancer, a GI cancer, a breast cancer, a prostate cancer, a lymphoma, a sarcoma, a melanoma, a cancer of the cervix or endometrium, a bladder cancer, a renal cancer, a liver cancer, or an ocular cancer. 
   
   
       37 . A method according to  claim 36  wherein the brain cancer is an astrocytoma. 
   
   
       38 . A method according to  claim 36  wherein the astrocytoma is glioblastoma multiforme. 
   
   
       39 . A method according to  claim 36  wherein the lung cancer is either a small cell lung carcinoma or a non small cell lung carcinoma. 
   
   
       40 . A method of potentiating radiotherapy cancer treatment according to  claim 19 , further comprising, administering daily doses of the radiosensitizer throughout the course of treatment. 
   
   
       41 . A method according to  claim 40  wherein the cancer is any of a brain cancer, a lung cancer, a head-and-neck cancer, a GI cancer, a breast cancer, a lymphoma, a melanoma, a prostate cancer, a bladder cancer, a kidney cancer, a liver cancer, a lo sarcoma, or an ocular cancer. 
   
   
       42 . A method according to  claim 40  wherein the brain cancer is the astrocytoma glioblastoma multiforme, and the method further comprises administering the radiosensitizer formulation daily by any suitable means including oral, intravenous, arterial infusion, intramuscular, intraperitoneal, subcutaneous, surgical, and topical. 
   
   
       43 . A method according to  claim 40 , wherein the head-and-neck cancer is squamous cell carcinoma or adenocarcinoma. 
   
   
       44 . A method according to  claim 40 , wherein the lung cancer is a small cell lung carcinoma or a non small cell lung carcinoma.