Compositions and methods for treating neoplastic diseases

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...

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Benefits of technology

[0107] Cell viability was assessed by 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; Chemicon International Inc., Temecula, Calif.) assay, according to manufacturer's instructions (Roche Molecular Biochemicals, Indianapolis, Ind.), and as described in 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; which is incorporated herein by reference in its entirety. Cell viability after treatment of MM.1S (-▪-), Dex-resistant MM.1R (-□-), RPMI-8226 (-●-), Doxorubicin-resistant Dox-40 (-♦-), OPM2 (-◯-), and U266 (-⋄-) cells with the compound of formula (II) (X=Cl) for 24 h is illustrated in FIG. 5A. Results are mean±S.D from three independent experiments (P<0.005; n=3 for all cell lines). A dose-dependent significant decrease in cell viability in all cell lines was observed (IC50 range 7-24 nM).

[0108] Cell viability was also assessed on purified patient MM cells. Freshly isolated tumor cells from nine MM patients relapsing after multiple prior therapies including Dex, Bortezomib, and thalidomide were treated with the compound of formula (II) (X=Cl) (10 nM) for 24 h and analyzed for apoptosis. As seen in FIG. 5B, significant apoptosis was observed in these cells as measured by DNA fragmentation assays (P<0.005; n=2). Plotted values are the mean±SD of triplicate samples. Importantly, 4 of 9 patients examined were refractory to Bortezomib therapy, and 5 patients were resistant to Thalidomide and Dex therapies. These data suggest that 1) the compound of formula (II) (X=Cl) induces apoptosis in MM cells sensitive and resistant to conventional and Bortezomib therapies; and 2) IC50 of the compound for MM cells is within the nanomolar concentration.

[0109] MM cells predominantly localize in the bone marrow microenvironment and their interaction with BMSCs induces production of cytokines which mediate growth of MM cells, as well as protect against drug-induced apoptosis. See Anderson, K. C. (2003) Cancer 97, 796-801; which is incorporated herein by reference in its entirety. Therefore, the effect of the compound of formula (II) (X=Cl) on five patient MM-derived BMSCs was determined. As seen in FIG. 6, treatment of BMSCs (Patient#1-5) with the compound of formula (II) (X=Cl) (20 nM) for 24 h does not induce apoptosis in these cells, as evidenced by DNA fragmentation assay. Positive control shown is an internal control for the assay. Purified MM cells (CD138+) from two of the five MM patient were also examined within the same experiments. Results are mean±SD from triplicate samples. The compound triggered a significant (10-12 fold) increase in apoptosis of purified (CD138-positive) patient MM cells. These results suggest that the compound of formula (II) (X=Cl) acts directly on MM cells, but not BMSCs.

[0110] Adhesion of MM cells to BMSCs induces IL-6 and IGF-I secretion from BMSCs, which not only regulates the growth of MM cells, but also protects against chemotherapy. See Hardin, J., MacLeod, S., Grigorieva, I., Chang, R., Barlogie, B., Xiao, H. & Epstein, J. (1994) Blood 84, 3063-70 and Chauhan, D., Kharbanda, S., Ogata, A., Urashima, M., Teoh, G., Robertson, M., Kufe, D. W. & Anderson, K. C. (...

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 res...

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