DNA intercalation and cleavage of an antitumor antibiotic dynemicin that contains anthracycline and enediyne cores

Dynemicin is a hybrid containing anthraquinone and enediyne cores, which contribute to binding and cleavage of DNA, respectively. DNA strand scission by the antitumor antibiotic is significantly enhanced by the addition of NADPH or thiol compounds. The preferential cutting site of dynemicin is on the 3' side of purine bases (i.e., 5'-GC, -GT, and -AG) and is clearly different from the cutting sites of esperamicin and calicheamicin. The double-stranded and the stem regions of single-stranded DNAs are preferentially cleaved by dynemicin. Therefore, dynemicin may be a useful reagent for probing secondary structures of DNA. Pretreatment of DNA with Adriamycin and actinomycin D alters the cutting mode of dynemicin. Dynemicin-mediated DNA breakage is strongly inhibited by pretreatment of the DNA with distamycin A and anthramycin, suggesting that dynemicin interacts with the minor groove of the DNA helix. Intercalation of the anthraquinone core into the DNA followed by the attack of the phenyl diradical formed from the enediyne core is considered as a possible mechanism of action of dynemicin

Efficacy and safety of monthly oral minodronate in patients with involutional osteoporosis

Summary Monthly minodronate at 30 or 50 mg had similar efficacy as 1 mg daily in terms of change in bone mineral density (BMD) and bone turnover markers with similar safety profiles. This new regimen provides patients with a new option for taking minodronate. Introduction Minodronate at a daily oral dose of 1 mg has been proven to have antivertebral fracture efficacy. In the present study, the efficacy and safety of oral minodronate at monthly doses of either 30 mg or 50 mg were compared with a daily dose of 1 mg. Methods A total of 692 patients with involutional osteoporosis were randomized to receive minodronate at either 30 or 50 mg monthly or a daily dose of 1 mg. The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at 12 months. Total hip BMD, bone turnover markers, serum calcium (Ca), and parathyroid hormone (PTH) levels were also evaluated. Results Minodronate at monthly doses of 30 or 50 mg were noninferior to the 1 mg daily dose in terms of change in LS-BMD. Changes in total hip BMD were also comparable. Although a transient decrease in serum Ca and increase in PTH levels were observed in all three groups at slightly different magnitudes and time courses, changes in bone turnover markers were comparable among the differentdosage groups with a similar time course. Safety profiles were also comparable. Conclusion Minodronate at monthly doses of 30 or 50 mg has similar efficacy to the daily 1 mg dose in terms of BMD and bone turnover markers with similar tolerability

The effect of once-yearly zoledronic acid on hip structural and biomechanical properties derived using computed tomography (CT) in Japanese women with osteoporosis

The effects of zoledronic acid on hip structural and biomechanical properties were evaluated in Japanese patients with osteoporosis by computed tomography (CT). The subjects included in this study were a subset of female subjects (zoledronic acid group, 49 subjects; placebo group, 53 subjects) in the phase 3 trial (ZONE study) who were available for multi-detector row CT (MDCT) scanning. Eligible subjects were those diagnosed with primary osteoporosis based on the Diagnostic Criteria for Primary Osteoporosis (2000) by the Japanese Society for Bone and Mineral Research and who had between one and four fractured vertebrae located between the fourth thoracic vertebra and the fourth lumbar vertebra. The subjects received a once-yearly intravenous infusion of zoledronic acid 5 mg or placebo for two years. CT data were obtained at baseline and at 12 and 24 months later and analyzed under blinded conditions. The results demonstrated that once-yearly intravenous infusion of zoledronic acid improved volumetric bone mineral density (vBMD), cortical bone geometry parameters, and CT-derived biomechanical parameters at the femoral neck, intertrochanteric region, and shaft; particularly at the intertrochanteric region, significant improvements in cortical bone geometry parameters and CT-derived biomechanical parameters, compared with those in the placebo group, were detectable early, at 12 months. The present data suggest that zoledronic acid has a possibility to reduce the risk of hip fractures in Japanese patients with osteoporosis

Effect of eldecalcitol, an active vitamin D analog, on hip structure and biomechanical properties: 3D assessment by clinical CT.

The effects of an active vitamin D analog, eldecalcitol (ELD), on bone mineral density (BMD), bone geometry, and biomechanical properties of the proximal femur were investigated by using clinical CT. The subjects - a subgroup of a recent randomized, double-blind study comparing anti-fracture efficacy of ELD with alfacalcidol (ALF) - constituted 193 ambulatory patients with osteoporosis (189 postmenopausal women and 4 men aged 52-85years, average±SD: 70.9±6.92years) enrolled at 11 institutions. Multidetector-row CT data was acquired at baseline and at completion of 144weeks\u27 treatment. Cross-sectional densitometric and geometric parameters of the femoral neck were derived from three-dimensional CT data. Biomechanical properties including cross-sectional moment of inertia (CSMI), section modulus (SM) and buckling ratio (BR) of the femoral neck, and CSMI of the femoral shaft were also calculated. We found that, 1) with respect to the femoral neck cross-sectional parameters (total bone), in the ALF group, volumetric BMD (vBMD) decreased but bone mass was maintained and cross-sectional area (CSA) increased. In contrast, ELD maintained vBMD with a significant increase in bone mass and a trend toward increased CSA. 2) With respect to the femoral neck cross-sectional parameters (cortex), cortical thickness decreased in the ALF group, but was maintained in the ELD group. In the ALF group, vBMD and bone mass increased, and CSA was maintained. In the ELD group, vBMD, CSA, and bone mass increased. 3) With respect to the biomechanical properties of the femoral neck, ELD improved CSMI and SM to a greater extent than did ALF. BR increased in both the ALF and ELD groups. 4) With respect to the femoral shaft parameters, overall the results of bone geometry and CSMI of the femoral shaft were very consistent with the results for the femoral neck; however, cortical vBMD of the femoral shaft decreased significantly in both the ELD and ALF groups. In conclusion, our longitudinal analysis of hip geometry by clinical CT revealed the unexpected potential of ELD to increase cortical CSA, vBMD, and bone mass, and to maintain cortical thickness, probably through the more potent effect of ELD in mitigating endocortical bone resorption than ALF. By improving the biomechanical properties of the proximal femur, ELD may have the potential to reduce the risk of hip fractures

Common Variants in a Novel Gene, FONG on Chromosome 2q33.1 Confer Risk of Osteoporosis in Japanese

Osteoporosis is a common disease characterized by low bone mass, decreased bone quality and increased predisposition to fracture. Genetic factors have been implicated in its etiology; however, the specific genes related to susceptibility to osteoporosis are not entirely known. To detect susceptibility genes for osteoporosis, we conducted a genome-wide association study in Japanese using ∼270,000 SNPs in 1,747 subjects (190 cases and 1,557 controls) followed by multiple levels of replication of the association using a total of ∼5,000 subjects (2,092 cases and 3,114 controls). Through these staged association studies followed by resequencing and linkage disequilibrium mapping, we identified a single nucleotide polymorphism (SNP), rs7605378 associated with osteoporosis. (combined P = 1.51×10−8, odds ratio = 1.25). This SNP is in a previously unknown gene on chromosome 2q33.1, FONG. FONG is predicted to encode a 147 amino-acid protein with a formiminotransferase domain in its N-terminal (FTCD_N domain) and is ubiquitously expressed in various tissues including bone. Our findings would give a new insight into osteoporosis etiology and pathogenesis

Randomized Teriparatide [Human Parathyroid Hormone (PTH) 1–34] Once-Weekly Efficacy Research (TOWER) Trial for Examining the Reduction in New Vertebral Fractures in Subjects with Primary Osteoporosis and High Fracture Risk

Context: Weekly teriparatide injection at a dose of 56.5 μg has been shown to increase bone mineral density. Objective: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. Design and Setting: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. Patients: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. Intervention: Subjects were randomly assigned to receive once-weekly sc injections of teriparatide (56.5 μg) or placebo for 72 wk. Main Outcome Measure: The primary endpoint was the incidence of new vertebral fracture. Results: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. Conclusion: Weekly sc administration of teriparatide at a dose of 56.5 μg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk