Effect of tyrosine kinase inhibitor sunitinib on tissue repair at tooth extraction sites.

BACKGROUND: Both zoledronic acid, a potent bisphosphonate, and the antiangiogenic drug sunitinib are included in anticancer protocols and have also been associated with jaw osteonecrosis. Our aim was to compare the effect of these drugs on tissue repair at tooth extraction sites. METHODS: Wistar rats were allocated into four groups: (1) sunitinib; (2) sunitinib/zoledronic acid; (3) zoledronic acid; (4) control group. The animals underwent tooth extractions and maxillae were macro- and microscopically analyzed. RESULTS: On macroscopic evaluation, the zoledronic acid group showed a significantly higher frequency of oral mucosal lesion; lesions in the sunitinib/zoledronic acid group were larger, albeit not significantly so. The sunitinib/zoledronic acid group had significantly less epithelium than the zoledronic acid and control group, but showed no significant difference compared to the sunitinib group. The sunitinib/zoledronic acid and zoledronic acid groups did not differ from each other, but had significantly less connective tissue and more non-vital bone and microbial colonies than sunitinib and control groups, whereas these latter two groups did not significantly differ from each other. Vital bone and inflammatory infiltrate did not significantly differ between groups. CONCLUSION: Sunitinib alone is not associated with non-vital bone, whereas the sunitinib/zoledronic acid combination and zoledronic acid alone are.

Evaluation of nuclear NF-κB, transglutaminase2, and ERCC1 as predictors of platinum resistance in testicular tumors

ABSTRACT Purpose: Testicular germ cells tumor (TGCT) are associated with a high cure rate and are treated with platinum-based chemotherapy. However, a group of testicular cancer patients may have a very unfavorable evolution and insensitivity to the main therapeutic agent chemotherapy (CT) cisplatin. The aim of this study was to evaluate the risk of recurrence and overall survival related to the expression of nuclear factor kappa-B (NF-κB), transglutaminase 2 (TG2) and excision repair cross-complementation group 1 (ERCC1) in patients with TGCT treated with platinum combinations. Patients and Methods: A retrospective study was performed with TGCT patients treated with platinum-based chemotherapy. Immunohistochemical analysis was performed and the expression was correlated with clinical and laboratory data. Results: Fifty patients were included, the mean age was 28.4 years (18 to 45), and 76% were non-seminoma. All patients were treated with standard cisplatin, etoposide and bleomycin or cisplatin, and etoposide. Patient's analyzed immunodetection for NF-κB, TG2, and ERCC1 were positive in 76%, 54% and 42%, respectively. Multivariate analysis identified that positive expressions to ERCC1 and NF-κB are independent risk factors for higher recurrence TGCT after chemotherapy (RR 2.96 and 3.16, respectively). Patients with positive expression of ERCC1 presented a poor overall survival rate for 10-year follow (p=0.001). Conclusions: The expression of ERCC1 and NF-κB give a worse prognosis for relapse, and only ERCC1 had an influence on the overall survival of TGCT patients treated with platinum-based chemotherapy. These may represent markers that predict poor clinical outcome and response to cisplatin.

Evaluation of nuclear NF-κB, transglutaminase2, and ERCC1 as predictors of platinum resistance in testicular tumors.

PURPOSE: Testicular germ cells tumor (TGCT) are associated with a high cure rate and are treated with platinum-based chemotherapy. However, a group of testicular cancer patients may have a very unfavorable evolution and insensitivity to the main therapeutic agent chemotherapy (CT) cisplatin. The aim of this study was to evaluate the risk of recurrence and overall survival related to the expression of nuclear factor kappa-B (NF-κB), transglutaminase 2 (TG2) and excision repair cross-complementation group 1 (ERCC1) in patients with TGCT treated with platinum combinations. PATIENTS AND METHODS: A retrospective study was performed with TGCT patients treated with platinum-based chemotherapy. Immunohistochemical analysis was performed and the expression was correlated with clinical and laboratory data. RESULTS: Fifty patients were included, the mean age was 28.4 years (18 to 45), and 76% were non-seminoma. All patients were treated with standard cisplatin, etoposide and bleomycin or cisplatin, and etoposide. Patient's analyzed immunodetection for NF-κB, TG2, and ERCC1 were positive in 76%, 54% and 42%, respectively. Multivariate analysis identified that positive expressions to ERCC1 and NF-κB are independent risk factors for higher recurrence TGCT after chemotherapy (RR 2.96 and 3.16, respectively). Patients with positive expression of ERCC1 presented a poor overall survival rate for 10-year follow (p=0.001). CONCLUSIONS: The expression of ERCC1 and NF-κB give a worse prognosis for relapse, and only ERCC1 had an influence on the overall survival of TGCT patients treated with platinum-based chemotherapy. These may represent markers that predict poor clinical outcome and response to cisplatin.

Comparison of effects of clodronate and zoledronic acid on the repair of maxilla surgical wounds - histomorphometric, receptor activator of nuclear factor-kB ligand, osteoprotegerin, von Willebrand factor, and caspase-3 evaluation.

BACKGROUND: The aim of this study was to compare clodronate and zoledronic acid regarding their influence on the repair of surgical wounds in maxillae (soft tissue wound and tooth extraction) and their relation to osteonecrosis. MATERIAL AND METHODS: Thirty-four Wistar rats were allocated into three groups according to the treatment received: (i) 12 animals treated with zoledronic acid, (ii) 12 animals treated with clodronate and (iii) 10 animals that were given saline solution. All animals were subjected to tooth extractions and surgically induced soft tissue injury. Histological analysis of the wound sites was performed by means of hematoxylin-eosin (H&E) staining and immunohistochemical staining for receptor activator of nuclear factor-kB ligand (RANKL), osteoprotegerin (OPG), von Willebrand factor, and caspase-3. RESULTS: The zoledronic acid group showed higher incidence of non-vital bone than did the clodronate group at the tooth extraction site. At the soft tissue wound site, there were no significant differences in non-vital bone between the test groups. RANKL, OPG, von Willebrand factor, and caspase-3 did not show significant differences between the groups for both sites of surgical procedures. CONCLUSION: Both of the bisphosphonates zoledronic acid and clodronate are capable of inducing maxillary osteonecrosis. Immunohistochemical analysis suggests that the involvement of soft tissues as the initiator of osteonecrosis development is less probable than has been pointed out.

Association between bisphosphonates and jaw osteonecrosis: a study in Wistar rats.

BACKGROUND: This work aimed at determining whether bisphosphonate therapy produces a sufficient condition for jaw osteonecrosis after tooth extraction. METHODS: Rats were allocated into 3 groups: (1) 11 rats treated with alendronate, (2) 10 rats treated with zoledronic acid, and (3) 10 control rats. The animals were subjected to tooth extractions, and at the end of bisphosphonate therapy, they were humanely killed. Histologic sections of the surgical site were processed and analyzed. RESULTS: The zoledronic acid group showed higher incidences of osteonecrosis, inflammatory infiltrate, and microorganisms. There was no significant difference for epithelial or connective tissue, root fragments, vital bone, and positive staining for vascular endothelial growth factor (VEGF) among the groups. CONCLUSION: Zoledronic acid is associated with jaw osteonecrosis, whereas alendronate did not produce a condition sufficient for osteonecrosis after tooth extraction. Neither zoledronic acid nor alendronate was associated with a reduced immunohistochemical expression of VEGF in vital bone at the tooth extraction site.

Toxicity of capecitabine compared with 5-fluorouracil in elderly patients with breast or gastrointestinal tract cancer

OBJECTIVES: The aim of this study was to evaluate the toxicity of capecitabine compared with 5-fluorouracil in elderly patients with breast or gastrointestinal tract cancer. MATERIAL AND METHODS: A cohort study was used to evaluate toxicity parameters in elderly patients undergoing chemotherapy treatment. This study was conducted between 2006 and 2008 and was composed of 76 patients from the Oncology Ambulatory of Hospital São Lucas, PUCRS. Eligible patients included elderly individuals (aged 60 years or above) of both sexes who suffered from breast or gastrointestinal tract cancer and who used daily oral capecitabine or intravenous 5-fluorouracil. General side effects were evaluated and graded on a four-point scale. The study also analyzed the values of blood markers such as alanine aminotransferase and aspartate aminotransferase for hepatic toxicity, and troponine I and electrocardiogram for cardiotoxicity. RESULTS: The data showed a higher frequency of general adverse effects in the patients who used 5-fluorouracil in relation of capecitabine. However, only the patients that used capecitabine suffered from hand-and-foot syndrome. Conversely, the levels of ALT in the elderly men who used capecitabine were significantly higher (p = 0.027) than those who used 5-fluorouracil. With regard to cardiac function, a significant difference (p = 0.023) in the median QT interval between the groups was found, while all the other exams presented normal results. CONCLUSION: The use of capecitabine should be frequently monitored in order to minimize or avoid the toxic effects of the chemotherapy in elderly patients. Other parameters should be subsequently analyzed to confirm this conclusion.

Differential ectonucleotidase expression in human bladder cancer cell lines.

Bladder cancer is the most prevalent tumor in the genitourinary tract. Nucleotides are important molecules that regulate many pathophysiological functions in the extracellular space. Studies have revealed evidence of a relationship between purinergic signaling and urothelial malignancies. Nucleotide-mediated signaling is controlled by a highly efficient enzymatic cascade, which includes the members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDases), ectonucleotide pyrophosphatase/phosphodiesterase (E-NPPs), ecto-alkaline phosphatases, and ecto-5'-nucleotidase/CD73. In an attempt to identify possible differential expression of ectonucleotidases during bladder cancer progression, a comparative analysis between RT4 (grade 1) and T24 (grade 3) bladder cancer cell lines was performed. In RT4 cells, the hydrolysis of tri- and diphosphate nucleosides was higher than monophosphonucleosides. T24 cells, however, presented the opposite profile, a low level of hydrolysis of tri- and diphosphate nucleosides and a high level of hydrolysis of monophosphates. Phosphodiesterase activity was negligible in both cell lines at physiological pH, indicating that these enzymes are not active under our assay conditions, although they are expressed in both cell lines. The T24 cells expressed NTPDase5 mRNA, while the RT4 cells expressed NTPDase3 and NTPDase5 mRNA. Both cell lines expressed ecto-5'-nucleotidase/CD73 mRNA. The present work describes, for the first time, the differential pattern of ectonucleotidases in the more malignant bladder cancer cells compared with cells derived from an early stage of bladder cancer. Our results open new avenues for research into the physiological roles of this family of enzymes and their possible therapeutic potential in bladder cancer.

Effect of temozolomide treatment on the adenine nucleotide hydrolysis in blood serum of rats with implanted gliomas

Objective: Adenine nucleotides and adenosine have many important functions in the physiological and pathological conditions. The measurement of these nucleotides in serum may be an auxiliary tool in the identification of cellular damage in many pathological conditions. The aim of this study is to examine the effect of chemotherapy treatment on nucleotide hydrolysis in the serum of rats following glioma implantation. Methods: C6 glioma cells were injected in the right striatum of 60 day-old Wistar rats, and 20 days after the induction of gliomas, blood serum samples were prepared for measurement of ATP and AMP hydrolysis. Results: The pathological analysis showed that the malignant gliomas induced by C6 injection and treated with temozolomide exhibited a reduction in malignant characteristics. The results demonstrated that the rats that underwent temozolomide treatment had a significant decrease (p<0.05) in blood serum hydrolysis of ATP and AMP when compared with the glioma group. None of the animals included in this study presented significant alterations in the activities of the serum enzymes alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Conclusion: The decrease in the enzymatic hydrolysis of the ATP and AMP is probably related to the diminished malignant characteristics caused by temozolomide treatment on the gliomas in vivo.

O antígeno prostático específico e sua importância na decisão clínica no câncer de próstata / The prostatic specific antigen and its importance in the clinical decision in the prostate cancer

O câncer de próstata (CaP) representa um problema de saúde pública de proporções cada vez mais importantes. É uma das neoplasias mais frequentes nos homens e representa uma das principais causas de morte na população. A busca de métodos diagnósticos para as neoplasias é um constante objetivo clínico laboratorial. Exame físico, métodos de imagem e dosagens laboratoriais compreendem o conjunto de auxílio diagnóstico no CaP. O antígeno prostático específico (PSA) é produzido pelo tecido prostático normal, bem como, em casos de Hiperplasia Prostática Benigna (HPB) e no CaP. Sua dosagem constitui importante método laboratorial na prática médica, uma vez que se apresenta com grande valor no rastreamento, diagnóstico e acompanhamento dos casos de CaP. O entendimento do seu papel pelo farmacêutico-bioquímico, bem como, a interação com a equipe clínica mostra-se promissor para influenciar as decisões diagnóstico-terapêuticas.

Prostate cancer represents a public health concern whose proportions are becoming increasingly important. It is one of the most common neoplasia among men and it represents one of the main causes of death in the population. The search for diagnostic methods for this neoplasia has been a constant laboratory clinic target. Physical checking, imaging methods and laboratory dosages compose the range of diagnostic support when dealing with prostate cancer...