In PMC 2011 1 July. July 2010, 47: 12 22 doi: 10.1016/j.bone.2010.03.006. PA Author Manuscript NIH-PA OSU-03012 AR-12 Author Manuscript NIH Author Manuscript NIH-PA L Sen of the two compounds, the on tumor cells and osteoclasts. This study examined the impact of our lead compound, MBC 11 5, phosphate and etidronate, bone tumor burden, bone volume, bone density of femur and overall survival in two different mouse models of TIBD, breast cancer and 4T1/luc KAS 1:06 MIP1 models with multiple myeloma. In M Inoculated mice with orthotopic Maus-Mamma-4T1/luc cells, MBC 11, the reduced H FREQUENCY doses of bone metastases in 40% vs. 90% and 100% of the PBS or the same M zoledronate treated Mice. MBC 11 was also significant bone tumor burden compared to M Mice treated PBS or zoledronate reduced.
PLX-4720 MBC 11 and zoledronate increased Ht fa If significant bone volume by two to four times larger It than that compared to M Mice treated PBS. In M Mice with human systemic multiple myeloma KAS 6/1 cells injected MIP1, 0.04 and 4.0 g / day MBC 11 femur bone density increase of 13% and 16%, respectively with PBS to 10 weeks compared to the injection of tumor cells and the median survival time increased hte to 95 days versus 77 days in M mice treated with PBS. Similar doses of zoledronate and the femur BMD has improved and increased Median survival time ht by 86 days, but it was not significantly different from PBS-treated M Mice. These results show that MBC 11 decreases bone tumor burden, h Lt bone structure and overall survival can be obtained hen, The continued development of the treatment of TIBD.
Schl��sselw Words bone cancer, bisphosphonates, chemotherapeutic agents, and drug conjugation of tumor-induced bone disease INTRODUCTION Targeting is a major cause of morbidity T and mortality T in cancer patients. It is found in 65% to 95% of patients with multiple myeloma and advanced breast cancer and prostate cancer. Because of significant morbidity associated with TIBD t and a median survival time of less than two years, the development of more effective therapies is justified. Bisphosphonates, particularly zoledronic acid, are bone-specific palliative treatments to reduce tumor-induced bone complications. Unfortunately TIBD proceeds even in patients with cancer requires the development of analogues with antiviral activity T and cytotoxic properties of absorption, improve the treatment of patients with TIBD.
As part of our tumor targeting, we used the bone seeking properties of bisphosphonates for the targeted delivery of chemotherapeutic agents. Bisphosphonates and cytotoxic drugs may be linked with F Is covalent, it does not affect blood flow and the conjugate of L You sen the two drugs in the bone microenvironment. We suggest that such conjugates the activity Th of bone resorption and antitumoral by the gel Walls combine the cell death induced bone tumors. Chemically, these compounds unique nucleoside 5, Similar triphosphate, and wherein the phosphorus atoms γ is held by a carbon-bonded oxygen atom. 1B shows the structures of conjugates with selected Hlten cytotoxic analogs or 5 fluorine arabinocytosine, based on the bisphosphonates, etidronate or medronate. MBC 11 with the release of hydrolysis etidronate AraC and 5, phosphate buffer-L Solutions with a concentration of pH, temperature and magnesium physiological