Claims
- 1. A pharmaceutical composition for treating a multi-drug resistant cell, comprising a competitor of hyaluronan interactions in an effective dose for reducing resistance of the cell to a drug.
- 2. The composition of claim 1, wherein the competitor of hyaluronan interactions is a hyaluronan receptor ligand or modulator selected from the group consisting of a glycosaminoglycan, a small molecule, an antibody, a soluble receptor, a hyaluronan binding construct, a hyaluronan mimetic, an inhibitor of hyaluronan synthesis, a stimulator of hyaluronan degradation, and and an inhibitor of receptor expression.
- 3. The composition of claim 2, wherein the glycosaminoglycan is a hyaluronan oligomer.
- 4. The composition of claim 3, wherein the oligomer contains at least 3 disaccharide subunits.
- 5. The composition of claim 3, wherein the oligomer contains at least 6 disaccharide subunits.
- 6. The composition of claim 3, wherein the oligomer contains less than 5,000 disaccharide subunits.
- 7. The composition of claim 3, wherein the oligomer contains less than 750 disaccharide subunits.
- 8. The composition of claim 3, wherein the oligomer contains less than 200 disaccharide subunits.
- 9. The composition of claim 3, wherein the hyaluronan oligomer is derivatized.
- 10. The composition of claim 9, wherein the derivatized hyaluronan oliomer is selected from the group consisting of alkylated, alkoxylated, and reduced.
- 11. The composition of claim 9, wherein the derivatized hyaluronan oliomer is selected from the group consisting of substituted with a carbodiimide, an N-(2-hydroxypropyl)methacrylamide, an amine, and a hydrazide.
- 12. The composition of claim 1, wherein the cell is a cancer cell or a bacterial cell.
- 13. The composition of claim 1, wherein the drug is an anti-cancer agent.
- 14. The composition of claim 1, wherein the drug is at least one anti-cancer agent selected from the group consisting of: γ-radiation, adriamycin, methotrexate, cisplatin, paclitaxel, docetaxel, doxorubicin, vinblastine, vincristine, BCNU, camptosar, 5-flurouracil, Velcade, fluorouracil, ZD0473, Gleevec, and oncovine.
- 15. The composition of claim 1, wherein the effective dose increases sensitivity of the cell to the drug by 40% to 90% compared to sensitivity of a control cell absent the ligand.
- 16. The composition of claim 1, wherein the effective dose increases sensitivity of the cell to the drug by 90% to 95% compared to sensitivity of a control cell absent the ligand.
- 17. The composition of claim 1, wherein the effective dose increases sensitivity of the cell to the drug by 90% to 99% compared to sensitivity of a control cell absent the ligand.
- 18. The composition of claim 13, further comprising the anti-cancer agent.
- 19. The composition of claim 1, further comprising an additional therapeutic agent.
- 20. The composition of claim 12, wherein the cell is selected from the group of cancers consisting of: melanoma; colon carcinoma; pancreatic; lymphoma; leukemia; glioma; lung; esophagus; mammary; prostate; head and neck; ovarian; kidney; and liver.
- 21. The composition of claim 12, wherein the cell is selected from the group of bacterial genera consisting of: Actinobacillus, Bacillus, Borrelia, Brucella, Campylobacter, Chlamydia, Clostridium, Coxiella, Enterococcus, Escherichia, Francisella, Hemophilus, Legionella, Mycobacterium, Neisseria, Pasteurella, Pneumophila, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, and Yersinia.
- 22. The composition of claim 1, wherein the effective dose is at least 1 mg/kg body weight.
- 23. The composition of claim 1, wherein the effective dose is at least 5 mg/kg body weight.
- 24. The composition of claim 1, wherein the effective dose is at least 10 mg/kg body weight.
- 25. The composition of claim 1, wherein the effective dose is 5 mg/kg body weight.
- 26. The composition of claim 1, further comprising a pharmaceutically acceptable excipient.
- 27. The composition of claim 19, wherein the additional therapeutic agent is selected from the group of agents consisting of: an anxiolytic, an anti-emetic, an anti-fatigue, a cytokine, an anti-infective, a potassium chelator; and an anti-hypertensive.
- 28. The composition of claim 19, wherein the additional therapeutic agent is a hematopoietic or erythropoietic agent.
- 29. The composition of claim 19, wherein the additional therapeutic agent is an inhibitor of multi-drug resistance.
- 30. The pharmaceutical composition of claim 29, wherein the inhibitor is at least one selected from the group consisting of: a verapamil, a cyclosporin A, a cyclosporin D, a reserpine analog, a trifluroperazine, a tamoxifen, a verapamil R isomer, a SDZ PSC-833, an MS-209, an S-9788, a_GF120918, and a LY3335979.
- 31. The composition of claim 2, wherein the hyaluronan receptor ligand or modulator is selected from the group consisting of an antibody decoy, a soluble receptor, a hyaluronan-binding link module construct, and an siRNA that inhibits expression of the receptor.
- 32. The composition of claim 31, wherein the antibody binds with high specificity and affinity to an hyaluronan receptor selected from the group consisting of: CD44, CD168 (RHAMM), HARE, lyve-1, layilin, and Toll-4.
- 33. Products containing an hyaluronan receptor ligand and an anticancer agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.
- 34. Products containing an hyaluronan oligomer and at least one anticancer agent as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.
- 35. A combination of an hyaluronan receptor ligand and an anti-cancer agent.
- 36. A combination of an hyaluronan oligomer and at least one anti-cancer agent.
- 37. A combination according to claims 35 or 36 formulated as a single composition.
- 38. A combination according to claims 35 or 36 formulated as separate compositions.
- 39. A method of preparing a medicament for treating a patient having a cancer, comprising formulating the medicament to contain the combination according to any of claims 35 to 38.
- 40. A method for treating a multi-drug resistant cancer, the method comprising: contacting a cell that has acquired resistance to at least one anti-cancer agent with a composition comprising a competitor of an hyaluronan interaction and the anti-cancer agent, wherein the competitor confers sensitivity to the anti-cancer agent on the cell, thereby treating the cancer.
- 41. A method for preparing a medicament for treating a multi-drug resistant cancer, the method comprising:
formulating the medicament to comprise a competitor of an hyaluronan interaction and an at least one anti-cancer agent; and contacting a cell that has acquired resistance to the at least one anti-cancer agent with the medicament, wherein the competitor confers sensitivity to the anti-cancer agent on the cell, thereby treating the cancer.
- 42. A method for treating a radiation resistant cancer, the method comprising: contacting a cell that has acquired resistance to at least one source of anti-cancer radiation with a composition comprising a competitor of an hyaluronan interaction and the at least one source of anti-cancer radiation, wherein the competitor confers sensitivity to the anti-cancer agent on the cell, thereby treating the cancer.
- 43. A method for preparing a medicament for treating a radiation-resistant cancer, the method comprising:
formulating the medicament to comprise a competitor of an hyaluronan interaction; and contacting a cell that has acquired resistance to the at least one source of anti-cancer radiation with the medicament and at least one source of anti-cancer radiation, wherein the competitor confers sensitivity to the anti-cancer radiation on the cell, thereby treating the cancer.
- 44. The method of any of claims 40-43, wherein the cell is a cancer cell in a subject.
- 45. The method of claim 44, wherein the competitor of an hyaluronan interaction is an hyaluronan oligomer.
- 46. The method of either of any of claims 40-45, further comprising evaluating progression of the cancer.
- 47. The method of claim 45, wherein contacting with the hyaluronan oligomer is administering a dose effective to confer sensitivity of the cell to the anti-cancer agent and inhibit growth or viability of the cell.
- 48. The method of claim 47, wherein the dose is an amount sufficient to induce programmed cell death in the cell.
- 49. A method of treating a multidrug resistant cancer comprising administering to a subject in need thereof a therapeutically effective dose of each of an anti-cancer agent and an hyaluronan receptor ligand.
- 50. A method for preparing a medicament for treating a multidrug resistant cancer, the method comprising formulating the medicament comprising a therapeutically effective dose of each of an anti-cancer agent and an hyaluronan receptor ligand, and administering the medicament to a subject the multidrug resistant cancer.
- 51. A method of treating a multidrug resistant cancer comprising administering to a subject in need thereof a therapeutically effective dose of each of an anti-cancer agent and an hyaluronan oligomer.
- 52. A method for preparing a medicament for treating a multidrug resistant cancer, the method comprising formulating the medicament comprising a therapeutically effective dose of each of an anti-cancer agent and an hyaluronan oligomer, and administering the medicament to a subject the multidrug resistant cancer.
- 53. The method of either of claims 51 or 52, wherein the anti-cancer agent and the hyaluronan oligomer are co-administered.
- 54. The method of either of claims 51 or 52, wherein the anti-cancer agent and the hyaluronan oligomer are administered sequentially.
- 55. The method of either of claims 51 or 52, wherein the cancer is selected from the group consisting of: melanoma; colon carcinoma; pancreatic; lymphoma; leukemia; glioma; lung; esophagus; mammary; prostate; head and neck; ovarian; kidney; and liver.
- 56. A method of evaluating a potential inhibitor of resistance of a cell to an anti-cancer therapeutic agent, the method comprising: contacting a first sample of a cell that has acquired resistance to the anti-cancer agent in the presence of the anti-cancer agent, and contacting a second sample of the cell in the presence of the anti-cancer agent and the potential inhibitor, wherein a reduction of an extent of a cell viability parameter by the potential anti-cancer agent in the second sample, compared to the extent in the first sample, and to a third control sample of the cell grown in the absence of the anti-cancer agent, is an indication that the potential inhibitor is an effective composition for treating resistance to the anti-cancer agent.
- 57. The method of claim 56, wherein the cell viability parameter is selected from the group consisting of: tumor size in vivo, anchorage independent colony formation, anchorage dependent colony formation, cell number, cellular macromolecular synthesis, programmed cell death, cellular caspase activity, cellular PI3 kinase activity, Akt phosphorylation, BAD phosphorylation, FKHR phosphorylation, Fas expression, and PTEN phosphatase activity.
- 58. A kit for treating a multi-drug resistant cell, the kit comprising a competitor of an hyaluronan interaction, and a container.
- 59. The kit of claim 58, further comprising at least one anti-cancer agent.
- 60. The kit of claim 58, wherein the competitor is an hyaluronan oligomer.
- 61. The kit of claim 59, wherein the anti-cancer agent is at least one selected from the group consisting of: γ-radiation, adriamycin, methotrexate, cisplatin, paclitaxel, docetaxel, doxorubicin, vinblastine, vincristine, BCNU, camptosar, 5-flurouracil, Velcade, ZD0473, Gleevec, and oncovine.
- 62. The kit of claim 58, further comprising instructions for use in administering the hyaluronan oligomer to treat a subject having the cell.
RELATED APPLICATIONS
[0001] This application claims the benefit of PCT application PCT/US03/20918 having a filing date of 1 Jul. 2003, and which claims priority to U.S. provisional application Ser. No. 60/392,905 filed Jul. 1, 2002, and U.S. provisional application Ser. No. 60/453,761 filed Mar. 11, 2003, each of which is hereby incorporated herein by reference in its entirety.
GOVERNMENT FUNDING
[0002] This invention was made in part with government support under grant CA73839 awarded by the National Institutes of Health. The government has certain rights in the invention.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60392905 |
Jul 2002 |
US |
|
60453761 |
Mar 2003 |
US |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
PCT/US03/20918 |
Jul 2003 |
US |
Child |
10835511 |
Apr 2004 |
US |