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Reinholz M.M.,Mayo Medical School | Zinnen S.P.,MBC Pharma Inc. | Dueck A.C.,Section of Biostatistics | Dingli D.,Mayo Medical School | And 21 more authors.
Bone | Year: 2010

Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced anti-resorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5'-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1α multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04μg/day; s.c.) reduced the incidence of bone metastases to 40% (4. /. 10), compared to 90% (9. /. 10; p=0.057) and 100% (5. /. 5; p=0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice (p=0.021, p=0.017, respectively). MBC-11 and zoledronate (0.04μg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice (p=0.005, p<0.001, respectively). In mice systemically injected with human multiple myeloma KAS-6/1-MIP1α cells, 0.04 and 4.0μg/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS (p=0.025, p=0.017, respectively) at 10. weeks post-tumor cell injection and increased mean survival to 95. days compared to 77. days in mice treated with PBS (p=0.047). Similar doses of zoledronate also improved femur BMD (p≤0.01 vs PBS) and increased mean survival to 86. days, but this was not significantly different than in PBS-treated mice (p=0.53). These results demonstrate that MBC-11 decreases bone tumor burden, maintains bone structure, and may increase overall survival, warranting further investigation as a treatment for TIBD. © 2010 Elsevier Inc.


Bren-Mattison Y.,University of Colorado at Boulder | Bren-Mattison Y.,MBC Pharma Inc. | Hausburg M.,University of Colorado at Boulder | Olwin B.B.,University of Colorado at Boulder
Developmental Biology | Year: 2011

During embryogenesis, muscle and bone develop in close temporal and spatial proximity. We show that Indian Hedgehog, a bone-derived signaling molecule, participates in growth of skeletal muscle. In Ihh -/- embryos, skeletal muscle development appears abnormal at embryonic day 14.5 and at later ages through embryonic day 20.5, dramatic losses of hindlimb muscle occur. To further examine the role of Ihh in myogenesis, we manipulated Ihh expression in the developing chick hindlimb. Reduction of Ihh in chicken embryo hindlimbs reduced skeletal muscle mass similar to that seen in Ihh -/- mouse embryos. The reduction in muscle mass appears to be a direct effect of Ihh since ectopic expression of Ihh by RCAS retroviral infection of chicken embryo hindlimbs restores muscle mass. These effects are independent of bone length, and occur when Shh is not expressed, suggesting Ihh acts directly on fetal myoblasts to regulate secondary myogenesis. Loss of muscle mass in Ihh null mouse embryos is accompanied by a dramatic increase in myoblast apoptosis by a loss of p21 protein. Our data suggest that Ihh promotes fetal myoblast survival during their differentiation into secondary myofibers by maintaining p21 protein levels. © 2011 Elsevier Inc.


Provided herein are compounds, compositions, and methods of using them to treat infections, neoplastic disease, inflammatory disease, and pain. Such compounds are nucleotides, acyclonucleotides, and ANP phosphonates conjugated with forms and/or moieties of Vitamin B6 for delivery past the cell membrane and into the cell.


Provided herein are compounds, compositions, and methods of using them to treat infections, neoplastic disease, inflammatory disease, and pain. Such compounds are nucleotides, acyclonucleotides, and ANP phosphonates conjugated with forms and/or moieties of Vitamin B6 for delivery past the cell membrane and into the cell.


Provided herein are compounds, compositions, and methods of using them to treat infections, neoplastic disease, inflammatory disease, and pain. Such compounds are nucleotides, acyclonucleotides, and ANP phosphonates conjugated with forms and/or moieties of Vitamin B6 for delivery past the cell membrane and into the cell.


Patent
MBC Pharma Inc. | Date: 2010-12-15

The present invention is directed to particular bisphosphonate compounds, and in particular, to bisphosphonate conjugates that are useful in the treatment of soft tissues surrounding bone and bone-related disease, and for diagnostic method.


The present invention provides novel bisphosphonate conjugates, pharmaceutical compositions comprising bisphosphonate conjugates and methods of using such analogs in the treatment of bone cancer, bone-related diseases, bone infection, bone inflammation, and diseases of the soft tissues surrounding bones.


The present invention provides novel bisphosphonate conjugates, pharmaceutical compositions comprising bisphosphonate conjugates and methods of using such analogs in the treatment of bone cancer, bone-related diseases, bone infection, bone inflammation, and diseases of the soft tissues surrounding bones.

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