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Compositions and methods for treating neoplastic diseases

a technology for neoplastic diseases and compositions, applied in the field of chemistry and medicine, can solve the problems of no treatment to overcome and cure the disease, and achieve the effects of reducing mm.1s cell viability, high serum levels, and increasing apoptosis

Inactive Publication Date: 2007-09-27
TRIPHASE RES & DEV I +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] Another aspect of the present invention is a method of treating a neoplastic disease, comprising administering to a patient inflicted with the neoplastic disease a synergistic combination of at least two proteosome inhibitors.

Problems solved by technology

Surgery and radiation therapy, however, are generally useful only for fairly defined types of cancer, and are of limited use for treating patients with disseminated disease.
Although chemotherapy can provide a therapeutic benefit, it often fails to result in cure of the disease due to the patient's cancer cells becoming resistant to the chemotherapeutic agent.
However, both intrinsic and acquired resistance has already been observed, and there are no therapies to overcome Bortezomib resistance at present.

Method used

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  • Compositions and methods for treating neoplastic diseases
  • Compositions and methods for treating neoplastic diseases
  • Compositions and methods for treating neoplastic diseases

Examples

Experimental program
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example 1

General Procedures

[0101] Cell culture and reagents. Dex-sensitive MM.11S and Dex-resistant MM.1R human MM cell lines were obtained from Dr. Steven Rosen (Northwestern University, Chicago, Ill.). See Moalli, P. A., Pillay, S., Weiner, D., Leikin, R. & Rosen, S. T. (1992) Blood 79, 213-22 and Chauhan, D., Catley, L., Hideshima, T., Li, G., Leblanc, R., Gupta, D., Sattler, M., Richardson, P., Schlossman, R. L., Podar, K., Weller, E., Munshi, N. & Anderson, K. C. (2002) Blood 100, 2187-94; both of which are incorporated herein by reference in their entirety. RPMI-8226 and Doxorubicin (Dox)-resistant (Dox-40) cells were obtained from Dr. William Dalton (Moffit Cancer Center, Tampa, Fla.). U266 and OPM2 MM cell lines were obtained from the American Type Culture Collection (Rockville, Md.). The human tumor cell lines DU 145, HT-29, Jurkat, LoVo, MDA-MB-231, MIA PaCa-2, NCI-H292, OVCAR-3, PANC-1, and PC-3 were purchased from ATCC (Manassas, Va.). MM Cell lines were grown in RPMI-1640 media...

example 2

In Vitro 20S Proteasome Activity Assay

[0103] The chymotrypsin-like activity of the 20S proteasome was measured as described in Stein, R. L., Melandri, F. & Dick, L. (1996) Biochemistry 35, 3899-908 and Lightcap, E. S., McCormack, T. A., Pien, C. S., Chau, V., Adams, J. & Elliott, P. J. (2000) Clin Chem 46, 673-83; both of which are incorporated herein by reference in their entirety. Purified human erythrocyte-derived 20S proteasome were obtained from Biomol, Plymouth Meeting, Pa. The chymotrypsin-like, caspase-like and trypsin-like activity activities of the 20S proteasome were determined using Suc-LLVY-AMC, Z-LLE-AMC (Boston Biochem, Cambridge, Mass.) and Boc-LRR-AMC (Bachem Bioscience, King of Prussia, Pa.) as peptide substrates, respectively. Fluorescence of the cleaved peptide substrate was measured using a Fluoroskan Ascent 96-well microplate reader (Thermo Electron, Waltham, Mass.). The EC50 values were calculated by Prism (GraphPad Software) using a sigmoidal dose-response, ...

example 3

Analysis of Ex Vivo 20S Proteasome Activity in Whole Blood Cells in Mice (Single I.V. or Oral Administration)

[0104] To directly determine whether the compound of formula (II) (X=Cl) inhibits proteasome activity in vivo, the compound of formula (II) (X=Cl) was dissolved in 100% DMSO and serially diluted with 5% Solutol (Solutol® HS 15; polyethylene glycol 660 12-hydroxystearate, BASF, Shreveport, La.) yielding a final concentration of 2% DMSO. The vehicle control consisted of 2% DMSO and 98% (5% Solutol® HS15). Male Swiss-Webster mice (five per group, 20-25 grams in weight) were treated at Bolder BioPATH, Inc. (Boulder, Colo.) with various concentrations of the compound either intravenously or orally at a volume of 10 mL / kg. One group of animals was untreated to establish a baseline of proteasome activity. Ninety minutes after administration of the compound, the animals were anesthetized and blood withdrawn by cardiac puncture. Packed whole blood cells were collected by centrifugati...

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Abstract

Disclosed herein are compositions and methods for treating neoplastic diseases. Included are compositions and methods that are effective against multiple myeloma cells resistant to conventional and bortezomib treatment. Furthermore, combination treatment with two different proteosome inhibitors is shown to be synergistic for treating multiple myeloma.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 633,161, filed Dec. 3, 2004, which is incorporated herein by reference in its entirety.STATEMENT OF GOVERNMENT INTEREST [0002] The work described herein was partially funded by NIH grants 50947, CA 78373, SPORE P50 CA100707-01, and P01 CA078378-06 and the U.S. government may have certain rights with regard to the present invention.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to the treatment of neoplastic diseases, such as cancer. [0005] 2. Description of the Related Art [0006] Cancer is a leading cause of death in the United States. Despite significant efforts to find new approaches for treating cancer, the primary treatment options remain surgery, chemotherapy and radiation therapy, either alone or in combination. Surger...

Claims

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Application Information

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IPC IPC(8): A61K31/407
CPCA61K31/397A61K31/407A61K31/454A61K31/573A61K31/69A61K45/06A61K31/704A61K2300/00A61P35/00A61P35/02A61P43/00A61K31/197A61K31/196
Inventor ANDERSON, KENNETH C.CHAUHAN, DHARMINDER
Owner TRIPHASE RES & DEV I
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