Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia / 癌症

Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

Bendamustine-induced immune hemolytic anemia in a chronic lymphocytic leukemia patient: a case report and review of the literature

Bendamustine is an alkylating agent approved for the treatment of chronic lymphocytic leukemia [CLL] and B-cell non-Hodgkin lymphoma. There are scant reports on bendamustine-induced immune hemolytic anemia occurring mainly in CLL patients. We report a case of immune hemolytic anemia that developed after exposure to bendamustine in a 70-year-old female with CLL who was previously exposed to fludarabine. Previous exposure to fludarabine is a common finding in the majority of reported cases of bendamustine drug-induced immune hemolytic anemia [DIIHA], including our case. Bendamustine should be suspected as the cause of any hemolytic anemia that develops while on this drug, especially in CLL patients treated previously with fludarabine

Design, synthesis and anti-proliferative activity of novel coumarin derivatives linking Schiff base and aryl nitrogen mustard / 药学学报

To explore novel coumarin derivatives with more potent anti-proliferative activity, a series of novel compounds were designed and synthesized by linking Schiff base and N, N-bis (2-chloroethyl) amine pharmacophore of nitrogen mustards to the coumarin's framework. Their structures were confirmed by 1H NMR, MS and element analysis techniques. In vitro anti-proliferative activities were evaluated against HepG2, DU145 and MCF7 cell lines by the standard MTT assay. The results showed that some of the target compounds exhibited strong anti-proliferative activities against selected tumor cells, and compounds 7c, 7f, 7g, 7h and 7q were better than or equal to the activities of positive control, they deserved further development.

Osseointegration of zirconia implant in the tibia of pigs / 대한치과보철학회지

PURPOSE: The purposes of this study were to investigate osseointegration around zirconia implants which had machined or alumina sandblasted surface, and to compare the results with titanium implants. MATERIALS AND METHODS: The study was performed on the tibia of 6 pigs. Three types of implants were investigated: group T-titanium implant, group Z-machined zirconia implant, group ZS-alumina sandblasting treated zirconia implant. Zirconia implants were manufactured from yttria-stabilized tetragonal zirconia polycrystalline (Acucera Inc., Pocheon, Korea). A total of 36 implants were installed in pigs' tibias. After 1, 4 and 12 weeks of healing period, the periotest and the histomorphometric analysis were performed. The data were analyzed using one-way ANOVA and significance was assessed by the Scheffe test (alpha=.05). RESULTS: In the measurement of surface roughness, highest Ra value was measured in group T with significant difference. No significant differences were found among groups regarding Periotest values. After 1 week, in comparison of bone to implant contact (BIC), group Z showed higher value with significant difference. In comparison of bone area (BA), group T and group Z showed higher value with significant difference than group ZS. After 4 weeks, in comparison of BIC, group T showed higher value with significant difference. Comparison of BA showed no significant difference among each implant. After 12 weeks, the highest mean BIC values were found in group T with significant difference. Group ZS showed higher BIC value with significant difference than group Z. In comparison of BA, group T and group ZS showed higher value with significant difference than group Z. CONCLUSION: Zirconia implant showed low levels of osseointegration in this experiment. Modification of surface structure should be taken into consideration in designing zirconia implants to improve the success rate.

Novel analysis model for implant osseointegration using ectopic bone formation via the recombinant human bone morphogenetic protein-2/macroporous biphasic calcium phosphate block system in rats: a proof-of-concept study

PURPOSE: The osseointegration around titanium mini-implants installed in macroporous biphasic calcium phosphate (MBCP) blocks was evaluated after incubation with recombinant human bone morphogenetic protein-2 (rhBMP-2) in an ectopic subcutaneous rat model. METHODS: Mini-implants (phi1.8x12 mm) were installed in MBCP blocks (bMBCPs, 4x5x15 mm) loaded with rhBMP-2 at 0.1 mg/mL, and then implanted for 8 weeks into subcutaneous pockets of male Sprague-Dawley rats (n=10). A histomorphometric analysis was performed, and the bone-to-implant contact (BIC) and bone density were evaluated. RESULTS: Significant osteoinductive activity was induced in the rhBMP-2/bMBCP group. The percentage of BIC was 41.23+/-4.13% (mean+/-standard deviation), while bone density was 33.47+/-5.73%. In contrast, no bone formation was observed in the bMBCP only group. CONCLUSIONS: This model represents a more standardized tool for analyzing osseointegration and bone healing along the implant surface and in bMBCPs that excludes various healing factors derived from selected animals and defect models.

Effect of bone-implant contact pattern on bone strain distribution: finite element method study / 대한치과보철학회지

PURPOSE: To date most of finite element analysis assumed the presence of 100% contact between bone and implant, which is inconsistent with clinical reality. In human retrieval study bone-implant contact (BIC) ratio ranged from 20 to 80%. The objective of this study was to explore the influence of bone-implant contact pattern on bone of the interface using nonlinear 3-dimensional finite element analysis. MATERIALS AND METHODS: A computer tomography-based finite element models with two types of implant (Mark III Branemark(R), Inplant(R)) which placed in the maxillary 2nd premolar area were constructed. Two different degrees of bone-implant contact ratio (40, 70%) each implant design were simulated. 5 finite element models were constructed each bone-implant contact ratio and implant design, and sum of models was 40. The position of bone-implant contact was determined according to random shuffle method. Elements of bone-implant contact in group W (wholly randomized osseointegration) was randomly selected in terms of total implant length including cortical and cancellous bone, while ones in group S (segmentally randomized osseointegration) was randomly selected each 0.75 mm vertically and horizontally. RESULTS: Maximum von Mises strain between group W and group S was not significantly different regardless of bone-implant contact ratio and implant design (P=.939). Peak von Mises strain of 40% BIC was significantly lower than one of 70% BIC (P=.007). There was no significant difference between Mark III Branemark(R) and Inplant(R) in 40% BIC, while average of peak von Mises strain for Inplant(R) was significantly lower (4886 +/- 1034 microm/m) compared with MK III Branemark(R) (7134 +/- 1232 microm/m) in BIC 70% (P<.0001). CONCLUSION: Assuming bone-implant contact in finite element method, whether the contact elements in bone were wholly randomly or segmentally randomly selected using random shuffle method, both methods could be effective to be no significant difference regardless of sample size.

Motor Evoked Potentials of the Upper Extremities in Healthy Children

OBJECTIVE: To evaluate and compare the organization of descending motor pathways to upper extremity muscles among healthy children. METHOD: The healthy children were 16 males and 7 females aged 1-19 years (average, 9 years), and eight healthy adults were enrolled as the control group. Transcranial magnetic stimulation was applied to bilateral motor cortices, and motor evoked potentials (MEPs) were recorded using surface electrodes from the first dorsal interossei (FDI), the biceps brachii (BIC), and the deltoid (DEL) muscles. The onset latency, central motor conduction time (CMCT), and amplitude were obtained during a relaxed state. RESULTS: MEPs of FDI were obtained from subjects aged 13 months. The frequency of obtaining MEPs in proximal and distal muscles increased with age, although there was a less frequent incidence of obtaining MEPs in the proximal BIC and DEL muscles compared with those in the distal FDI muscle. MEP amplitudes increased with age, whereas latencies were relatively constant. CMCTs showed a similar pattern of maturation, and adult values were obtained by 13-years-of-age. CONCLUSION: These results suggest that the proximal and distal muscles of the upper extremities show different maturation and organization patterns.

Experimental study about the bony healing of hydroxyapatite coating implants

INTRODUCTION: Hydroxyapatite(HA) coating implant can accelerate osseointegration, however, there are many controversies. MATERIALS AND METHODS: This study examined the early osseointegration of two types of hydroxyapatite coated implants. Twelve adult male miniature pigs (Medi Kinetics Micropigs, Medi Kinetics Co., Ltd., Busan, Korea) were used in this study. In the implants placed in the mandible, a histomorphometric evaluation was performed to evaluate the bone-implant contact (BIC) ratio. RESULTS: The BIC ratio increased with time. TS III HA and Zimmer HA were not significantly different (P>0.05). At 8 weeks, the BIC of Zimmer HA was higher than TS III HA, but there was no significant difference (P>0.05). CONCLUSION: HA coated implants will accelerate early osseointegration.

Effect on bone healing by the application of low intensity pulsed ultrasound after injection of adipose tissue-derived stem cells at the implantation of titanium implant in the tibia of diabetes-induced rat

INTRODUCTION: This study examined the effect of the application of low intensity pulsed ultrasound on bone healing after an injection of adipose tissue-derived stem cells (ADSCs) during the implantation of a titanium implant in the tibia of diabetes-induced rats. MATERIALS AND METHODS: Twelve Sprague-Dawely rats were used. After inducing diabetes, the ADSCs were injected into the hole for the implant. Customized screw type implants, 2.0 mm in diameter and 3.5 mm in length, were implanted in both the tibia of the diabetes-induced rats. After implantation, LIPUS was applied with parameters of 3 MHz, 40 mW/cm2 , and 10 minutes for 7 days to the left tibiae (experimental group) of the diabetes-induced rats. The right tibiae in each rat were used in the control group. At 1, 2 and 4 week rats were sacrificed, and the bone tissues of both tibia were harvested. The bone tissues of the three rats in each week were used for bone-to-implant contact (BIC) and bone area (BA) analyses and the bone tissues of one rat were used to make sagittal serial sections. RESULTS: In histomorphometric analyses, the BIC in the experimental and control group were respectively, 39.00+/-18.17% and 42.87+/-9.27% at 1 week, 43.74+/-6.83% and 32.27+/-6.00% at 2 weeks, and 32.62+/-11.02% and 47.10+/-9.77% at 4 weeks. The BA in experimental and control group were respectively, 37.28+/-3.68% and 31.90+/-2.84% at 1 week, 20.62+/-2.47% and 15.64+/-2.69% at 2 weeks, and 11.37+/-4.54% and 17.69+/-8.77% at 4 weeks. In immunohistochemistry analyses, Osteoprotegerin expression was strong at 1 and 2 weeks in the experimental group than the control group. Receptor activator of nuclear factor kB ligand expression showed similar staining at each week in the experimental and control group. CONCLUSION: These results suggest that the application of low intensity pulsed ultrasound after an injection of adipose tissue-derived stem cells during the implantation of titanium implants in the tibia of diabetes-induced rats provided some positive effect on bone regeneration at the early stage after implantation. On the other hand, this method is unable to increase the level of osseointegration and bone regeneration of the implant in an uncontrolled diabetic patient.

Comparative Study on Osseointegration of Calcium Metaphosphate (CMP) Coated Implant to RBM Implant in the Femur of Rabbits

Effect of intrathecal glycine and related amino acids on the allodynia and hyperalgesic action of strychnine or bicuculline in mice / 대한마취과학회지

BACKGROUND: The intrathecal (IT) administration of glycine or GABAA receptor antagonist result in a touch evoked allodynia through disinhibition in the spinal cord. Glycine is an inhibitory neurotransmitter that appears to be important in sensory processing in the spinal cord. This study was aimed to evaluate the effect of glycine-related amino acids on antagonizing the effects of IT strychnine (STR) or bicuculline (BIC) when each amino acid was administered in combination with STR or BIC. METHODS: A total of 174 male ICR mice were randomized to receive an IT injection of equimolar dose of glycine, betaine, beta-alanine, or taurine in combination with STR or BIC. Agitation in response to innocuous stimulation with a von Frey filament after IT injection was assessed. The pain index in hot-plate test were observed after it injection. The effect of it muscimol in combination with str or bic were also observed. RESULTS: The allodynia induced by STR was relieved by high dose of glycine or betaine. But, allodynia induced by BIC was not relieved by any amino acid. Whereas the STR-induced thermal hyperalgesia was only relieved by high dose of taurine at 120 min after IT injection, the BIC-induced one was relieved by not only high dose of taurine at 120 min but also low dose of glycine or betaine at 60 min after IT injection. The BIC-induced allodynia and thermal hyperalgesia was relieved by IT muscimol. CONCLUSIONS: This study suggests that IT glycine and related amino acids can reduce the allodynic and hyperalgesic action of STR or BIC in mice.

Study of the re-osseointegration of implant fixture after mechanical unscrewing / 대한치과보철학회지

PURPOSE: The purpose of this study was to investigate whether the re-osseointegration of the implants that had mechanical unscrewing possibly occurred or not. Furthermore, if it happened, the degree of re-osseointegration was evaluated by comparing with previous osseointegration. MATERIALS AND METHODS: The smooth implant (commercial pure titanium 99%) specimens, whose diameter and length was 3.75 mm, 4 mm, respectively were produced. Two implants were inserted into each tibia of 7 New Zealand female white rabbits weighing at least 3.0 kg. The torque removal force for each implant after 6 weeks of implants placement was measured and included in group I . The torque removal forces were assessed after the fixtures were re-screwed to original position and the subjects were allowed to have 4 more weeks for healing and included in group II. One rabbit was sacrificed after first measurement and produced 4 slide specimens in group I, and two rabbits were sacrificed after 2nd measurement, 7 slide specimens, in group II for histomorphologic investigations. All slide specimens were assessed based on the proportion of BIC (bone-implant contact) as well as CBa (Bone area in the cortical passage) value produced by counting the screw threads embedded in the compact bones under the optical microscopic analysis (x20). Statistical analysis was conducted to evaluate the torque removal force, BIC and CBa between group I and II. RESULTS: As for the torque removal force, the result was 10.8 +/- 3.6 Ncm for group I and 20.2 +/- 9.7 Ncm for group II. Furthermore, the torque removal force of group II increased by 98.1% in average compared to group I (P .05), and RT/BIC and RT/CBa between group I and group II were statistically significant (P < .05). CONCLUSION: It is possible to obtain more substantial re-osseointegration within shorter periods than the period needed for the initial osseointegration in case of iatrogenically unscrewed implants.

Marginal bony changes in relation to different vertical positions of dental implants

PURPOSE: The purpose of this study was to radiographically evaluate marginal bony changes in relation to different vertical positions of dental implants. METHODS: Two hundred implants placed in 107 patients were examined. The implants were classified by the vertical positions of the fixture-abutment connection (microgap): 'bone level,' 'above bone level,' or 'below bone level.' Marginal bone levels were examined in the radiographs taken immediately after fixture insertion, immediately after second-stage surgery, 6 months after prosthesis insertion, and 1 year after prosthesis insertion. Radiographic evaluation was carried out by measuring the distance between the microgap and the most coronal bone-to-implant contact (BIC). RESULTS: Immediately after fixture insertion, the distance between the microgap and most coronal BIC was 0.06 +/- 0.68 mm; at second surgery, 0.43 +/- 0.83 mm; 6 months after loading, 1.36 +/- 0.56 mm; and 1 year after loading, 1.53 +/- 0.51 mm (mean +/- SD). All bony changes were statistically significant but the difference between the second surgery and the 6-month loading was greater than between other periods. In the 'below bone level' group, the marginal bony change between fixture insertion and 1 year after loading was about 2.25 mm, and in the 'bone level' group, 1.47 mm, and in 'above bone level' group, 0.89 mm. Therefore, the marginal bony change was smaller than other groups in the 'above bone level' group and larger than other groups in the 'below bone level' group. CONCLUSIONS: Our results demonstrated that marginal bony changes occur during the early phase of healing after implant placement. These changes are dependent on the vertical positions of implants.

Histomorphometric study of machined titanium implants and calcium phosphate coated titanium implants / 대한치과보철학회지

PURPOSE: The objective of this study was to investigate the effects of calcium phosphate coated titanium implant surface on bone response and implant stability at early stage of healing period of 3 weeks and later healing period of 6 weeks. MATERIAL AND METHODS: A total of 24 machined, screw-shaped implants (Dentium Co., Ltd., Seoul, Korea) which dimensions were 3.3 mm in diameter and 5.0 mm in length, were used in this research. All implants (n = 24), made of commercially pure (grade IV) titanium, were divided into 2 groups. Twelve implants (n = 12) were machined without any surface modification (control). The test implants (n = 12) were anodized and coated with thin film (150 nm) of calcium phosphate by electron-beam deposition. The implants were placed on the proximal surface of the rabbit tibiae. The bone to implant contact (BIC) ratios was evaluated after 3 and 6 weeks of implant insertion. RESULTS: The BIC percentage of calcium phosphate coated implants (70.8 +/- 18.9%) was significantly higher than that of machined implants (44.1 +/- 16.5%) 3 weeks after implant insertion (P = 0.0264). However, there was no significant difference between the groups after 6 weeks of healing (P > .05). CONCLUSION: The histomorphometric evaluation of implant surface revealed that: 1. After 3 weeks early healing period, bone to implant contact (BIC) percentage of calcium phosphate coated implants (70.8%) was much greater than that of surface untreated machined implants (44.1%) with P = 0.0264. 2. After 6 weeks healing period, however, BIC percentage of calcium phosphate coated implants group (79.0%) was similar to the machined only implant group (78.6%). There was no statistical difference between two groups (P = 0.8074). 3. We found the significant deference between the control group and experimental group during the early healing period of 3 weeks. But no statistical difference was found between two groups during the later of 6 weeks.

A histomorphometric study of dental implants with different surface characteristics

PURPOSE: One of the major keys to achieve successful osseointegration of the implant is its surface properties. The aim of this study was to investigate the bone response to dental implants with different surface characteristics using the rabbit tibia model. Tricalcium phosphate (TCP) coated, anodic oxidized and turned (control) surfaces were compared. MATERIALS AND METHODS: Seventy two implants were placed in the tibia of eighteen rabbits. Nine rabbits were sacrificed at 3 weeks of healing and the remaining nine were sacrificed at 6 weeks of healing. The bone-to-implant contact (BIC) and the bone volume density (BVD) were assessed by light microscope after 3 and 6 weeks of healing. RESULTS: Statistical analysis showed that no significant differences in the BIC and BVD were observed between the different implant surfaces and the control group at 3 weeks and 6 weeks of healing. Data also suggested that the BVD of all the surfaces showed significant difference at 3 and 6 weeks. CONCLUSION: The present study has showed that osseointegration occurred in all investigated types of surface-treated implants. In the current study all of the threads of the implants were observed to calculate BIC and BVD values (instead of choosing some of the threads from the bone cortex for example), which didn't make BIC or BVD percentage values better than in the control group, therefore the clinical relevance of these results remains to be shown.

Effect of RHPDGF-BB and RhBMP-2 on Osseointegration of Titanium Implants at Periimplant Bone Defects Grafted with Hydroxyapatite: Micro-Ct and Histologic Analysis

A histomorphometric study on the effect of surface treatment on the osseointegration / 대한치과보철학회지

STATEMENT OF PROBLEM: Many studies have been conducted to improve the primary stability of implants by providing bioactive surfaces via surface treatments. Increase of surface roughness may increase osteoblast activity and promote stronger bonding between bone and implant surface and it has been reported that bioactive surface or titanium can be obtained through alkali and heat treatment. PURPOSE: The purpose of this study was to evaluate the stability of alkali and heat treated implants via histomorphometric analysis. MATERIAL AND METHODS: Specimens were divided into three groups; group 1 was the control group with machined surface, the other groups were treated for 24 hours in 5 M NaOH solution and heat treated for 1 hour at 600degrees C in the atmosphere (group 2) and vacuum (group 3) conditions respectively. Surface characteristics were analyzed and fixtures were implanted into rabbits. The specimens were histologically and histomorphometrically compared according to healing periods and change in bone composition were analyzed with EPMA (Electron Probe Micro Analyzer). RESULTS: 1. Groups treated with alkali and heat showed increase of oxidization layer and Na ions. Groups 2 which was heat treated in atmosphere showed significant increase of surface roughness (P<.05). 2. Histomorphometric analysis showed significant increase in BIC (bone to implant contact) according to increase in healing period and there was significant increases in groups 2 and 3 (P<.05). 3. BA(bone area) ratio showed similar results as contact ratio, but according to statistical analysis there was significant increase according to increase in healing period in group 2 only (P<.05). 4. EPMA analysis revealed no difference in gradation of bone composition of K, P, Ca, Ti in surrounding bone of implants according to healing periods but groups 2 and 3 showed increase of Ca and P in the initial stages. CONCLUSION: From the results above, it can be considered that alkali and heat treated implants in the atmosphere have advantages in osseointegration in early stages and may decrease the time interval between implantation and functional adaptation.

The Influence of the Initial Stability After Dental Implant Installation on the Osseointegration

The effect of loading time on the stability of mini-implant / 대한치과교정학회지

OBJECTIVE: The purpose of this study was to investigate the stability of mini-implants in relation to loading time. METHODS: A total of 48 mini-implants (ORLUS, Ortholution, Korea) were placed into the buccal alveolar bone of the mandible in 8 male beagle dogs. Orthodontic force (200 - 250 gm) was applied immediately for the immediate loading group while force application was delayed for 3 weeks in the delayed loading group. For the subsequent loading periods (3, 6, 12 weeks), BIC (bone implant contact) and BV/TV (bone volume/total volume) and mobility test were carried out. RESULTS: The immediate loading group showed no changes in BIC from 3 to 12 weeks, while the delayed loading group showed a significant increase in BIC between 3 and 12 weeks (p < 0.05). The BV/TV of the delayed loading group significantly increased from 6 to 12 weeks of loading (p < 0.05), while the BV/TV of the immediate loading group decreased from 3 to 12 weeks of loading. However, there was no significant difference in BV/TV between experimental groups. The mobility of the immediate loading group was not significantly different from that of the delayed loading group after 12 weeks of loading (p < 0.05). CONCLUSIONS: These results showed that immediate loading does not have a negative effect on the stability of mini-implants compared to the early loading method in both the clinical and histomorphometric point of view.

Bone-implant contact and mobility of surface-treated orthodontic micro-implants in dogs / 대한치과교정학회지

OBJECTIVE: The purpose of this study was to evaluate the mobility and ratio of the bone-implant contact (BIC) of a sandblasted, large grit and acid-etched (SLA) orthodontic micro-implant. METHODS: Ninety-six micro-implants (48 SLA and 48 machined) were implanted in the upper and lower buccal alveolar bone, and palatal bone of four beagle dogs. Two weeks after surgery, orthodontic force (150 - 200 g) was applied. Two beagles were sacrificed at 4-weeks and the other two at 12-weeks. Histomorphometric comparisons were made between the SLA experimental group and the machined micro-implant as a control group to determine the ratio of contact between the bone and implant. Micro-implant mobility was also evaluated using Periotest(R). RESULTS: Periotest values showed no statistically significant difference in the upper alveolar and palatal bone between groups except for the lower buccal area. BIC in the upper buccal area showed no significant difference between groups both at 4-weeks and 12-weeks. However, both the groups showed a significant difference in BIC ratio in the rest of the experimental areas between 4 weeks and 12 weeks. The experimental group showed active bone remodeling around the bone-implant interface compared to the control group. CONCLUSIONS: There were significant differences in the BIC and the Periotest values between the surface-treated and machined micro-implants according to bone quality in the early stage.