Methods And Compositions For Cancer Therapies That Include Delivery Of Halogenated Thymidines And Thymidine Phosphorylase Inhibitors In Combination With Radiation

Abstract

Methods and formulations are provided for treating cancer and neoplastic diseases in conjunction with radiation therapy where such methods and formulations include a combination of a radiosensitizing agent that is metabolized by thymidine phosphorylase and a thymidine phosphorylase inhibitor that increases the half-life of the radiosensitizing agent.

What is claimed is: 
     
         1 . A method for sensitizing cancer cells in a patient having cancer to radiation therapy, the method comprising the steps of:
 a. administering a therapeutically effective amount of a radiosensitizing agent that is metabolized by thymidine phosphorylase to the patient to sensitize cancerous cells to radiation, the radiosensitizing agent comprising 5-iodo-2′-deoxyuridine (IUdR) or a prodrug thereof; and   b. administering a selected effective amount of a thymidine phosphorylase inhibitor to the patient that is configured to inhibit thymidine phosphorylase to hinder metabolization of the radiosensitizing agent by thymidine phosphorylase.   
     
     
         2 . A method for treating cancer in a patient in need of such treatment by irradiating cancerous cells in the patient, the method comprising the steps of:
 a. administering a therapeutically effective amount of a radiosensitizing agent that is metabolized by thymidine phosphorylase to the patient to sensitize cancerous cells to radiation, the radiosensitizing agent comprising 5-iodo-2′-deoxyuridine (IUdR) or a prodrug thereof;   b. administering a selected effective amount of a thymidine phosphorylase inhibitor to the patient that is configured to inhibit thymidine phosphorylase to hinder metabolization of the radiosensitizing agent by thymidine phosphorylase; and   c. irradiating a selected tissue of the patient that comprises sensitized cancerous cells.   
     
     
         3 . The method of any  one of the preceding claims , wherein the thymidine phosphorylase inhibitor comprises Tipiracil. 
     
     
         4 . The method of  any one of the preceding claims , wherein the cancer comprises one or more of pancreatic cancer, hepatic cancer, prostate cancer, colorectal cancer, breast cancer, gastric cancer, non-small-cell lung cancer, metastatic breast cancer, head and neck cancers, endometrial cancer, ovarian cancer, ureter cancer, cervical cancer, esophageal cancer, bladder cancer, small-cell cancer, non-small-cell cancer, malignant lymphomas, and brain cancer, rectal cancer, and sarcomas. 
     
     
         5 . The method of  any one of the preceding claims , wherein the cancer is one or more of rectal cancer and brain cancer. 
     
     
         6 . The method of any one of  claims 1 to 3 , wherein the cancer comprises a pediatric cancer selected from the group consisting of leukemia, lymphoma, Hodgkin’s disease, rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma, dysgerminomas, Wilm’s tumor, retinoblastoma, ependymoma, and medulloblastoma. 
     
     
         7 . The method of  any one of the preceding claims , wherein the selected tissue comprises a surgically resected selected tissue. 
     
     
         8 . The method of  claim 2 , comprising the step of repeating one or more of steps (a), (b), and (c). 
     
     
         9 . The method of  any one of the preceding claims , wherein the step of administering a therapeutically effective amount of a radiosensitizing agent comprises a route of administration selected from the group consisting of oral, parenteral, liposome-mediated, rectal, vaginal, inhalation, insufflation, transdermal, intravenous, otic, and combinations thereof. 
     
     
         10 . The method of  any one of the preceding claims , wherein the step of administering a therapeutically effective amount of a radiosensitizing agent comprises orally or intravenously administering a therapeutically effective amount of the radiosensitizing agent. 
     
     
         11 . The method of any one of the preceding claims, wherein the step of administering a selected effective amount of a thymidine phosphorylase inhibitor comprises a route of administration selected from the group consisting of oral, parenteral, liposome-mediated, rectal, vaginal, inhalation, insufflation, transdermal, intravenous, otic, and combinations thereof. 
     
     
         12 . The method of  any one of the preceding claims , wherein the step of administering a selected effective amount of a thymidine phosphorylase inhibitor comprises orally or intravenously administering a selected effective amount of the thymidine phosphorylase inhibitor. 
     
     
         13 . The method of  any one of the preceding claims , wherein the radiosensitizing agent is IUdR. 
     
     
         14 . The method of  any one of the preceding claims , wherein the prodrug comprises 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR). 
     
     
         15 . The method of any one  claims 1-13 , wherein the radiosensitizing agent comprises 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR). 
     
     
         16 . The method of  any one of the preceding claims , wherein the therapeutically effective amount of the radiosensitizing agent and the selected effective amount of the thymidine phosphorylase inhibitor are administered simultaneously or sequentially to the patient. 
     
     
         17 . The method of  any one of the preceding claims , wherein the therapeutically effective amount of the radiosensitizing agent and the selected effective amount of the thymidine phosphorylase inhibitor are administered simultaneously to the patient. 
     
     
         18 . The method of  any one of the preceding claims , comprising the step of administering a therapeutically effective amount of a radiomimetic therapeutic agent. 
     
     
         19 . The method of  claim 18 , wherein the radiomimetic agent comprises cis-platinum. 
     
     
         20 . A kit for providing a method for treating cancer in a patient in need of such treatment by irradiating cancerous cells in the patient, the kit comprising 5-iodo-2′-deoxyuridine (IUdR) or a prodrug thereof, a thymidine phosphorylase inhibitor, and instructions for use of the IUdR or prodrug thereof and the thymidine phosphorylase inhibitor in combination with radiation therapy for treating cancer in the patient in need of such treatment. 
     
     
         21 . The kit of  claim 20 , wherein the thymidine phosphorylase inhibitor comprises Tipiracil. 
     
     
         22 . The kit of  claim 20  or  21 , wherein the cancer comprises one or more of pancreatic cancer, hepatic cancer, prostate cancer, colorectal cancer, breast cancer, gastric cancer, non-small-cell lung cancer, metastatic breast cancer, head and neck cancers, endometrial cancer, ovarian cancer, ureter cancer, cervical cancer, esophageal cancer, bladder cancer, small-cell cancer, non-small-cell cancer, malignant lymphomas, and brain cancer, rectal cancer, and sarcomas. 
     
     
         23 . The kit of any one of  claims 20-22 , wherein the cancer is one or more of rectal cancer and brain cancer. 
     
     
         24 . The kit of  claim 20  or  21 , wherein the cancer comprises a pediatric cancer selected from the group consisting of leukemia, lymphoma, Hodgkin’s disease, rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma, dysgerminomas, Wilm’s tumor, retinoblastoma, ependymoma, and medulloblastoma. 
     
     
         25 . The kit of any one of  claims 20-24 , comprising a radiomimetic therapeutic agent. 
     
     
         26 . The kit of  claim 25 , wherein the radiomimetic therapeutic agent comprises cis-platinum. 
     
     
         27 . The kit of any one of  claims 20-26 , wherein the prodrug comprises 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR). 
     
     
         28 . A pharmaceutical composition for sensitizing cancerous cells to radiation therapy, the composition comprising:
 a. a radiosensitizing agent that is metabolized by thymidine phosphorylase, wherein the radiosensitizing agent comprises 5-iodo-2′-deoxyuridine (IUdR) or a prodrug thereof;   b. a thymidine phosphorylase inhibitor that hinders metabolism of the radiosensitizing agent by thymidine phosphorylase; and   c. a physiologically compatible carrier medium.   
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the thymidine phosphorylase inhibitor comprises Tipiracil. 
     
     
         30 . The pharmaceutical composition of  claim 28  or  29 , wherein the physiologically compatible carrier medium comprises one or more of a solvent, diluent, liquid vehicle, dispersion aid, suspension aid, surface agent, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder, lubricant, and filler. 
     
     
         31 . The pharmaceutical composition of any one of  claims 28-30 , comprising a radiomimetic therapeutic agent. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the radiomimetic therapeutic agent comprises cis-platinum. 
     
     
         33 . The pharmaceutical composition of any one of  claims 28-32 , wherein the prodrug comprises 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR). 
     
     
         34 . The pharmaceutical composition of any one of  claims 28-32 , wherein the radiosensitizing agent comprises 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR). 
     
     
         35 . The pharmaceutical composition of any one of  claims 28-34 , wherein the pharmaceutical composition is prepared as an orally administered dosage unit. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the orally administered dosage unit comprises a solid dosage form. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the solid dosage form comprises a multicomponent tablet. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the multicomponent comprises:
 a. an inner component comprising the radiosensitizing agent and a first physiologically compatible carrier medium; and   b. an outer component disposed around the inner component comprising the thymidine phosphorylase inhibitor and a second physiologically compatible carrier medium.