Dataset Information

A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites.

ABSTRACT: 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-MIP1alpha multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 microg/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 (0.04 microg/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-MIP1alpha cells, 0.04 and 4.0 microg/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< or =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.

SUBMITTER: Reinholz MM

PROVIDER: S-EPMC2892200 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites.

Reinholz Monica M MM Zinnen Shawn P SP Dueck Amylou C AC Dingli David D Reinholz Gregory G GG Jonart Leslie A LA Kitzmann Kathleen A KA Bruzek Amy K AK Negron Vivian V Abdalla Abdalla K AK Arendt Bonnie K BK Croatt Anthony J AJ Sanchez-Perez Luis L Sebesta David P DP Lönnberg Harri H Yoneda Toshiyuki T Nath Karl A KA Jelinek Diane F DF Russell Stephen J SJ Ingle James N JN Spelsberg Thomas C TC Dixon Henry B F Hal HB Karpeisky Alexander A Lingle Wilma L WL

Bone 20100315 1

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 lea ...[more]

PMID: 20233612

Similar Datasets

Project description:In exploring nature's potential in addressing liver-related conditions, this study investigates the therapeutic capabilities of flavonoids. Utilizing in silico methodologies, we focus on flavone and its analogs (1-14) to assess their therapeutic potential in treating liver diseases. Molecular change calculations using density functional theory (DFT) were conducted on these compounds, accompanied by an evaluation of each analog's physiochemical and biochemical properties. The study further assesses these flavonoids' binding effectiveness and locations through molecular docking studies against six target proteins associated with human cancer. Tropoflavin and taxifolin served as reference drugs. The structurally modified flavone analogs (1-14) displayed a broad range of binding affinities, ranging from -7.0 to -9.4 kcal mol⁻¹, surpassing the reference drugs. Notably, flavonoid (7) exhibited significantly higher binding affinities with proteins Nrf2 (PDB:1 × 2 J) and DCK (PDB:1 × 2 J) (-9.4 and -8.1 kcal mol⁻¹) compared to tropoflavin (-9.3 and -8.0 kcal mol⁻¹) and taxifolin (-9.4 and -7.1 kcal mol⁻¹), respectively. Molecular dynamics (MD) simulations revealed that the docked complexes had a root mean square deviation (RMSD) value ranging from 0.05 to 0.2 nm and a root mean square fluctuation (RMSF) value between 0.35 and 1.3 nm during perturbation. The study concludes that 5,7-dihydroxyflavone (7) shows substantial promise as a potential therapeutic agent for liver-related conditions. However, further validation through in vitro and in vivo studies is necessary. Key insights from this study include:•Screening of flavanols and their derivatives to determine pharmacological and bioactive properties using ADMET, molinspiration, and pass prediction analysis.•Docking of shortlisted flavone derivatives with proteins having essential functions.•Analysis of the best protein-flavonoid docked complexes using molecular dynamics simulation to determine the flavonoid's efficiency and stability within a system.

Project description:BackgroundImplant loosening is associated with inflammatory bone loss induced by ultra-high molecular weight polyethylene wear debris. We hypothesized that a hydroxyapatite-bisphosphonate composite improves periprosthetic bone quality and osseous integration of an intramedullary implant even in the presence of ultra-high molecular weight polyethylene particles in an experimental rat femur model.MethodsA preliminary in vitro study determined the optimal concentration of zoledronate (50 microM) that would maximally decrease osteoclasts without harming osteoblasts. Hydroxyapatite-coated intramedullary nails were implanted bilaterally in the femora of sixteen rats (the control group), and hydroxyapatite-zoledronate-coated nails were implanted bilaterally in the femora of sixteen rats (the experimental group). Ultra-high molecular weight polyethylene particles were introduced into the femoral canal before implantation. Eight rats from each group were killed at six weeks, and the remaining rats were killed at six months. Periprosthetic bone mass was analyzed by dual x-ray absorptiometry and microcomputed tomography. Osseous integration was examined by biomechanical testing of pullout strength.ResultsThe mean bone area (and standard deviation) in the periprosthetic bone region was significantly greater (p < 0.0001) in the hydroxyapatite-zoledronate group (2.388 +/- 0.960 mm2) than in the control group (0.933 +/- 0.571 mm2). This difference was larger in the six-week group than in the six-month group (p = 0.03). The average peak pullout force for the treated femora (241.0 +/- 95.1 N) was significantly greater (p < 0.0001) than that for the controls (55.6 +/- 49.0 N). This difference was similar in the six-week and six-month groups. The energy required for nail pullout was significantly greater (p < 0.0001) for the treated femora (521.6 +/- 293.8 N-mm) than for the controls (142.2 +/- 152.1 N-mm). This difference in energy to pullout was similar in the six-week and six-month groups. Regression analysis demonstrated a high correlation between periprosthetic bone mass and peak pullout force for both the six-week (r = 0.766, p = 0.0005) and six-month (r = 0.838, p < 0.0001) groups.ConclusionsSurface modification of implants with hydroxyapatite-zoledronate improves periprosthetic bone quality and osseous integration.Clinical relevanceHydroxyapatite-based site-specific delivery of bisphosphonates may be one way of reducing ultra-high molecular weight polyethylene wear particle-induced periprosthetic osteolysis and implant loosening.

Dataset Information

A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites.

Publications

A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets