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Details for Patent: 6,344,447

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Details for Patent: 6,344,447

Title: Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides
Abstract:The subject invention discloses compounds, compositions and methods for treatment and prevention of toxicity due to chemotherapeutic agents and antiviral agents. Disclosed are acylated derivatives of non-methylated pyrimidine nucleosides. These compounds are capable of attenuating damage to the hematopoietic system in animals receiving antiviral or antineoplastic chemotherapy.
Inventor(s): von Borstel; Reid W. (Potomac, MD), Bamat; Michael K. (Potomac, MD)
Assignee: Pro-Neuron, Inc. (Gaithersburg, MD)
Filing Date:Feb 16, 1999
Application Number:09/249,790
Claims:1. A method for treating cancer comprising:

(a) administering a pyrimidine nucleoside analog in a dose at least 1.5 fold greater than the normal maximum tolerated dose, and

(b) administering a pharmaceutically effective amount of an acyl derivative of a non-methylated pyrimidine nucleoside selected from the group consisting of an acyl derivative of uridine, an acyl derivative of cytidine, an acyl derivative of 2'-deoxycytidine and an acyl derivative of 2'-deoxyuridine;

wherein the cancer is selected from the group consisting of melanoma, prostate cancer, renal carcinoma, ovarian carcinoma, lung cancer and tumors of the colon, rectum, stomach, pancreas, breast, head and neck.

2. The method as in claim 1 wherein said pyrimidine nucleoside analog is selected from the group consisting of 5-fluorouracil (5-FU), 5-FU prodrugs, prodrug derivatives of fluorouridine or 2'-deoxyfluorouridine, fluorocytosine, trifluoro-methyl-2'-deoxyuridine, arabinosyl cytosine, prodrugs of arabinosyl cytosine, cyclocytidine, 5-aza-2'-deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-aspartic acid (PALA), pyrazofurin, 6-azauridine, azaribine, thymidine, and 3-deazauridine.

3. The method as in claim 1 wherein said pyrimidine nucleoside analog is a 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog and said acyl derivative of a non-methylated pyrimidine nucleoside is an acyl derivative of uridine, cytidine, or deoxyuridine.

4. The method as in claim 3 wherein said 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog is selected from the group consisting of 5-fluorouracil, 5-fluorouracil prodrugs fluorouridine, 2'-deoxyfluorouridine, prodrug derivatives of fluorouridine, prodrug derivatives of 2'-deoxyfluorouridine, 5-fluorocytosine, 5-fluorocytidine, or prodrug derivatives of 5-fluorocytidine.

5. The method as in claim 3 wherein said 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog is 5-fluorouracil.

6. The method as in claim 5 wherein said administering step (a) comprises administering a bolus of 900 to 2400 mg/m.sup.2 of 5-fluorouracil, and said administering step (b) comprises administering 2 to 24 hours after step (a) 1 to 10 grams of an acyl derivative of a nonmethylated pyrimidine nucleoside, wherein steps (a) and (b) are repeated 3-6 times.

7. The method as in claim 6 wherein the time interval between each repetition of step (a) is 4 to 14 days.

8. The method as in claim 5 wherein said administering step (a) comprises administering a bolus of 600 to 1000 mg/m.sup.2 of 5-fluorouracil daily for 4 to 5 consecutive days, and said administering step (b) comprises administering 2 to 12 hours after each step (a) 1 to 10 grams of an acyl derivative of a nonmethylated pyrimidine nucleoside.

9. The method as in claim 1 wherein said pyrimidine nucleoside analog is N-phosphonoacetyl-L-aspartic acid (PALA), pyrazofurin, 6-azauridine, azaribine, trifluoro-methyl-2'-deoxyuridine, or 3-deazauridine and said acyl derivative of a non-methylated pyrimidine nucleoside is an acyl derivative of uridine or cytidine.

10. The method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is triacetyluridine.

11. The method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is ethoxycarbonyluridine.

12. The method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is triacetylcytidine.

13. The method as in claim 1 wherein said acyl derivative of a non-methylated pyrimidine nucleoside is diacetyldeoxycytidine.

14. The method as in claim 1 wherein said pyrimidine nucleoside analog is an antineoplastic analog of cytidine and said acyl derivative of a non-methylated pyrimidine nucleoside is an acyl derivative of deoxycytidine.

15. The method as in claim 14 wherein said antineoplastic analog of cytidine is arabinosyl cytosine or prodrugs thereof, cyclocytidine, 5-aza-2'-deoxycytidine, arabinosyl 5-azacytosine, or 6-azacytidine.

16. The method as in claim 1 wherein said pyrimidine nucleoside analog is an analog of uridine, said acylated derivative of a non-methylated pyrimidine nucleoside is an acylated derivative of uridine, deoxyuridine, or cytidine, and said administering step (b) also includes administering an inhibitor of uridine phosphorylase.

17. The method as in claim 16 wherein said inhibitor of uridine phosphorylase is selected from the group consisting of benzylacyclouridine, benzyloxybenzylacyclouridine, aminomethyl-benzylacyclouridine, aminomethylbenzyloxybenzylacyclouridine, hydroxymethylbenzylacyclouridine, hydroxymethyl-benzyloxybenzylacyclouridine, 2,2'-anhydro-5-ethyluridine, 5-benzyl barbiturate, 5-benzyloxybenzyl barbiturate, 5-benzyloxybenzyl-1-[(1-hydroxy-2-ethoxy)methyl] barbiturate, 5-benzyloxybenzylacetyl-1-[(1-hydroxy-2-ethoxy)methyl]barbiturate, and 5-methoxybenzylacetylacyclobarbiturate.

18. The method as in claim 1 wherein said acylated derivative of a non-methylated pyrimidine nucleoside is an acylated derivative of cytidine or deoxycytidine, and said administering step (b) also includes administering an inhibitor of cytidine deaminase.

19. The method as in claim 18 wherein said inhibitor of cytidine deaminase is selected from the group consisting of tetrahydrouridine or tetrahydro-2'-deoxyuridine.

20. The method as in claim 1 wherein said acylated derivative of a non-methylated pyrimidine nucleoside is an acylated derivative of uridine, cytidine or deoxycytidine, and said administering step (b) also includes administering an inhibitor of nucleoside transport.

21. The method as in claim 20 wherein said inhibitor of nucleoside transport is selected from the group consisting of dilazep, dipyridamole, probenicid, lidoflazine and nitrobenzylthioinosine.

22. The method as in claim 1 wherein said administering step (b) also includes administering an agent which enhances hematopoiesis.

23. The method as in claim 1 wherein said administering step (b) also includes administering a compound capable of enhancing the uptake and phosphorylation of nucleosides into cells.

24. The method as in claim 1 wherein said administering step (a) also includes administering AZT.

25. The method as in claim 1 wherein said fluorinated pyrimidine is administered in conjunction with a biochemical modulator of 5-fluorouracil efficacy.

26. The method as in claim 25 wherein said modulator is an inhibitor of purine biosynthesis, an antifolate, an inhibitor of pyrimidine biosynthesis, or an inhibitor of 5-fluorouracil degradation.

27. The method as in claim 26 wherein said inhibitor of purine biosynthesis is methylmercaptopurine riboside.

28. The method as in claim 26 wherein said antifolate is methotrexate or trimetrexate.

29. The method as in claim 26 wherein said inhibitor of pyrimidine biosynthesis is PALA, brequinar, acivicin, or 6-azauridine.

30. The method as in claim 26 wherein said inhibitor of 5-fluorouracil degradation is an inhibitor of the enzyme dihydropyrimidine dehydrogenase.

31. The method as in claim 30 wherein said inhibitor of dihydropyrimidine dehydrogenase is 5-ethynyluracil, bromovinyluracil, CDHP, uracil, thymine, thymidine or benzyloxybenzyluracil.

32. A method for treating cancer comprising:

(a) administering an inhibitor of the enzyme dihydropyrimidine dehydrogenase;

(b) administering a 5-fluoropyrimidine or 5-fluoropyrimidin nucleoside analog;

(c) administering a pharmaceutically effective amount of an acyl derivative of a non-methylated pyrimidine nucleoside selected from the group consisting of an acyl derivative of uridine, an acyl derivative of cytidine, an acyl derivative of 2'-deoxycytidine and an acyl derivative of 2'-deoxyuridine;

wherein the cancer is selected from the group consisting of tumors of the colon, rectum, stomach, pancreas, breast, head and neck.

33. The method as in claim 32 wherein said 5-fluoropyrimidine or 5-fluoropyrimidine nucleoside analog is selected from the group consisting of 5-fluorouracil, 5-fluorouracil prodrugs fluorouridine, 2'-deoxyfluorouridine, prodrug derivatives of fluorouridine, prodrug derivatives of 2'-deoxyfluorouridine, 5-fluorocytosine, 5-fluorocytidine, and prodrug derivatives of 5-fluorocytidine.

34. The method as in claim 32 wherein said inhibitor of dihydropyrimidine dehydrogenase is 5-ethynyluracil, bromovinyluracil, cyanodidhydropyridine, uracil, thymine, thymidine or benzyloxybenzyluracil.

35. The method as in claim 32 wherein said administering step (a) takes place before or at the same time as said administering step (b).

36. A method according to claim 1, wherein the cancer is pancreatic cancer.

37. The method as in claim 2 wherein said 5-FU prodrugs are selected from the group consisting of tegafur, 5'-deoxyfluorouridine, fluorouridine and 2'-deoxyfluorouridine.

38. The method as in claim 4 wherein said 5-fluorouracil prodrugs are selected from the group consisting of tegafur, 5'-deoxyfluorouridine, fluorouridine and 2'-deoxyfluorouridine.

39. The method as in claim 33 wherein said 5-fluorouracil prodrugs are selected from the group consisting of tegafur, 5'-deoxyfluorouridine, fluorouridine and 2'-deoxyfluorouridine.
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