Search PubMed⌕ Search

Biomedical subjects

Gilberto Schwartsmann

Publications and source records attributed to Gilberto Schwartsmann.

At least 37 records · Page 2Linked to original sources
PubMed2004

The bombesin/gastrin releasing peptide receptor antagonist RC-3095 blocks apomorphine but not MK-801-induced stereotypy in mice.

Bombesin (BN)-like peptides might be involved in the pathogenesis of neuropsychiatric disorders such as schizophrenia. Stereotyped behaviors induced by the dopamine receptor agonist apomorphine or the N-methyl-D-aspartate glutamate receptor antagonist dizocilpine (MK-801) in rodents have been proposed as animal models of schizophrenic psychosis. In the present study we evaluated the effects of the BN/gastrin-releasing peptide receptor (GRP) antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) on apomorphine and MK-801-induced stereotyped behavior in mice. An intraperitoneal (i.p.) injection of RC-3095 (1.0, 10.0 or 100.0 mg/kg) blocked apomorphine-induced stereotypy. The inhibitory effect of RC-3095 on apomorhine-induced stereotypy was similar to that induced by haloperidol (0.5 mg/kg). RC-3095 did not affect stereotyped behavior induced by MK-801 (0.5 mg/kg). The results provide the first evidence that BN/GRP receptor antagonism blocks stereotyped behavior induced by a dopamine agonist. Together with previous evidence, the present study indicates that the BN/GRP receptor can be considered a drug target in the investigation of potential new agents for treating neuropsychiatric disorders.

Animals↗
PubMed2004

Phase II study of thalidomide in patients with metastatic malignant melanoma.

Thalidomide has anti-angiogenic and immunomodulatory activity, exhibiting antitumour effects in patients with multiple myeloma and, more rarely, in several other solid tumours. We evaluated the single-agent antitumour activity and toxicity profile of thalidomide in patients with metastatic malignant melanoma, as well as its plasma pharmacokinetics and pharmacodynamic effects [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) levels]. A two-stage Gehan method was used with a stopping rule after 14 consecutive non-responding patients. Thalidomide was given orally at a daily dose of 200 mg/day, which was then escalated every 2 weeks by 200 mg/day as tolerated to a maximum of 800 mg/day. Patients were evaluated every 8 weeks for response using the World Health Organization (WHO)-27 criteria. Fourteen patients were enrolled and no objective responses were observed, with one stable disease and one mixed response. The dose-limiting toxicities were constipation, dizziness and somnolence. Other toxicities were oedema, neuropathy, dry skin, dry mouth, tremor and fatigue. The plasma pharmacokinetics of thalidomide were comparable with those of previous studies in normal volunteers and in patients with advanced prostate cancer. Serum levels of b-FGF and VEGF did not change significantly following drug administration. In conclusion, thalidomide showed poor activity, but acceptable toxicity, in patients with metastatic melanoma. Future studies should explore this agent in combination with other biological agents or cytotoxic agents, such as temozolomide.

Administration, Oral↗
PubMed2004

Bombesin/gastrin-releasing peptide receptors in the basolateral amygdala regulate memory consolidation.

Several receptor and intracellular signalling systems in the basolateral amygdala (BLA) regulate memory formation. In the present study, we show that bombesin/gastrin-releasing peptide (GRP) receptors in the BLA are involved in the consolidation of affectively motivated memory. Adult male rats were trained in a single-trial step-down inhibitory avoidance task and tested for retention 24 h later. Post-training systemic injection of the bombesin/GRP receptor antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) impaired memory retention. In rats implanted under thionembutal anaesthesia with guide cannulae aimed at the BLA, post-training bilateral infusion of RC-3095 into the BLA dose-dependently impaired retention. Pre-training unilateral muscimol inactivation of the BLA blocked the memory-impairing effect of post-training systemic administration of RC-3095. The results suggest that bombesin/GRP receptors in the BLA are involved in the consolidation of aversive memory, and the BLA mediates the memory-impairing effect of systemic bombesin/GRP receptor blockade.

Amygdala↗
PubMed2004

Radioresistance is associated to increased Hsp70 content in human glioblastoma cell lines.

Radiation therapy is routinely prescribed for high-grade malignant gliomas. However, the efficacy of this therapeutic modality is often limited by the occurrence of radioresistance, reflected as a diminished susceptibility of the irradiated cells to undergo apoptosis. Heat-shock proteins (Hsps) synthesis can be increased by cellular insults, such as radiation-induced damage. Inducible Hsp70 has been suggested to have multiple roles in cytoprotection against apoptosis. Accordingly, high levels of Hsp70 prevent stress-induced apoptosis. In the present study, we investigated whether the content of Hsp70 is associated to glioblastoma cell radioresistance. To this end, the U-87MG, U-251MG and MO59J human glioblastoma cell lines were irradiated at 2, 5 and 10 Gy and their relative radioresistance and Hsp70 were determined. Following 5 Gy irradiation, in MO59J and U-251MG a significant decrease in colony formation was found, whereas the U-87MG was relatively radioresistant. Three hours after the irradiation (at 5 Gy) Hsp70 contents increased 110% in the U-87 MG cells, but did not significantly change in the U-251MG and MO59J cells. Thus, our results suggest that Hsp70 protection against radiation-induced apoptosis might underlie glioblastoma radioresistance.

Apoptosis↗
PubMed2003

Altered extracellular ATP, ADP and AMP catabolism in glioma cell lines.

In order to characterize the enzymes involved in the purine nucleotide catabolism as indicators of invasiveness and aggressiveness of malignant gliomas, the degradation of extracellular nucleotides by five different glioma cell lines was investigated and compared with primary astrocytes. Rapid hydrolysis of extracellular ATP and ADP by astrocytes was observed, whereas all glioma cell lines examined presented low rates of ATP hydrolysis. In contrast, ecto-5'-nucleotidase activity was increased in glioma cell lines when compared to astrocytes. Considering that ATP is recognized as a mitogenic factor that induces proliferation in human glioma cells, the substantial decrease in ATP and ADP hydrolysis observed in gliomas leads us to suggest that alterations in the ecto-nucleotidases pathway may represent an important mechanism associated with malignant transformation of glioma cell lines.

5'-Nucleotidase↗
PubMed2003

Sentinel lymph node procedure in patients with epidermoid carcinoma of the anal canal: early experience.

PURPOSE: This study was conducted to assess the feasibility of the sentinel lymph node procedure in patients with epidermoid carcinoma of the anal canal. METHODS: Between February 2001 and November 2002, 14 patients with epidermoid carcinoma of the anal canal and no clinical evidence of inguinal involvement were prospectively enrolled in the study. The sentinel lymph node procedure consisted of a combination of preoperative lymphoscintigraphy with technetium 99m dextran 500 injected around the tumor and intraoperative detection of the sentinel node with a gamma probe. Patent blue V dye was also injected at the periphery of the tumor to facilitate direct identification of the blue-stained lymph node. After removal, the sentinel node was studied by hematoxylin and eosin staining and immunohistochemistry for pancytokeratins (antigen A1 and A3). RESULTS: Detection and removal of sentinel lymph nodes was possible in all patients. There was no correlation between tumor size and pattern of lymphatic drainage to the groin. Tumors located in the midline of the anal canal gave rise to bilateral sentinel nodes in eight of nine cases. In total, 23 sentinel lymph nodes were removed. One patient (7.1 percent) had a node identified as positive for metastatic carcinoma on immunohistochemical staining. Surgical complications were minimal. CONCLUSIONS: The standardized technique was safe and highly effective in sampling inguinal sentinel lymph nodes in carcinoma of the anal canal. It also proved to be useful as an instrument to detect micrometastatic deposits in clinically normal nodes. Our early results suggest the sentinel lymph node procedure may have a role in guiding a more selective approach for patients with anal cancer. Additional studies in a larger patient population to determine the sensitivity and specificity of this method are warranted.

Aged↗
PubMed2003

Intrahippocampal infusion of the bombesin/gastrin-releasing peptide antagonist RC-3095 impairs inhibitory avoidance retention.

Bombesin (BN)-like peptides regulate cell proliferation and cancer growth as well as neuroendocrine and neural functions. We evaluated the effects of the BN/gastrin-releasing peptide (GRP) antagonist RC-3095 on memory formation. Male Wistar rats were given a bilateral infusion of saline or RC-3095 (0.2, 1.0 or 5.0 microg) into the dorsal hippocampus either immediately or 2 h after training in an inhibitory avoidance (IA) task. Retention test trials were carried out 1.5 h (short-term memory) and 24 h (long-term memory) after training. RC-3095 impaired both short- and long-term retention only when given immediately after training. The results suggest that the hippocampal BN/GRP receptor system modulates IA memory formation.

Animals↗
PubMed2003

Modulation of oxidative stress in response to gamma-radiation in human glioma cell lines.

Radiation therapy is routinely used in the management of primary central nervous system malignancies. However, the efficacy of this therapeutic modality is limited by the occurrence of resistance. In the present study, we investigated whether modulation of oxidative stress might underlie glioma cell radioresistance. Superoxide dismutase activity in irradiated M059J cells was two-fold higher than that in untreated controls, but did not significantly change in U-87 and U-138 cells. This is accompanied by an increase in reactive oxygen species content and decreases in cells viability. Pharmacological or genetic modulation of oxidative stress could be associated with an enhancement in the susceptibility of tumor cells to radiation therapy.

Animals↗
PubMed2003

Phase II trial and pharmacokinetic study of thalidomide in patients with metastatic colorectal cancer.

INTRODUCTION: This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. STUDY DESIGN: This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. PATIENTS AND METHODS: Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200 mg/day of thalidomide with an increase in dose by 200 mg/day every 2 weeks until a final daily dose of 800 mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200 mg level and in one patient at 600 mg during the first 24 h. MAIN OUTCOME MEASURES AND RESULTS: A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.

Adult↗
PubMed2003

Extracellular nucleotides and nucleosides induce proliferation and increase nucleoside transport in human glioma cell lines.

Extracellular purines (adenosine triphosphate (ATP), adenosine 5'-diphosphate (ADP) and adenosine) and pyrimidines (uridine 5'-triphosphate (UTP) and UDP) are important signaling molecules that mediate diverse biological effects via P1 and P2 purinergic receptors. The human glioma cell lines U87 MG, U251 MG and U138 MG were treated with purines and pyrimidines for 24 or 48 h and proliferation was measured by [3H]-thymidine incorporation, flow cytometry and cell counting. The studies showed that extracellular nucleotides and nucleosides induce proliferation of the studied glioma cells. Incorporation of [3H]-thymidine followed the order of ATP approximately equal to guanosine approximately equal to inosine approximately equal to adenosine > UTP > ADP while ATPgammaS and 2MeSATP had no effect. The effect of ATP was partially inhibited by suramin and by reactive blue 2 (RB2). Co-treatment with the following antagonists of P1 purinoreceptors DPCPX, CPT or 8PT did not block the effect of adenosine while a specific antagonist of the A3 receptor, MRS1220, totally blocked the effect of adenosine. ATP and adenosine also increased the overall uptake of [3H]-thymidine into the cell, producing a positive effect on the [3H]-thymidine incorporation measurements. These data indicate that the uptake of thymidine and proliferation of gliomas can be induced by purines and pyrimidines via both P1 and P2 purinoceptors.

Adenosine↗
PubMed2003

High-dose chemotherapy and autologous peripheral blood stem cell rescue in a patient with pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) is a rare and aggressive malignant tumor of the lung. Approximately 80 cases of PPB have been published, and in only three cases high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) was applied. A 5-year-old girl presenting with cough, fever, and shortness of breath was referred to the authors in March 1999. A computed tomography scan of the chest showed a tumor mass in the left hemithorax. The lesion was biopsied and the histopathologic report suggested the diagnosis of PPB. The patient received chemotherapy comprising vincristine, actinomycin D, and cyclophosphamide with only a minor response, and treatment was switched to ifosfamide, carboplatin, and etoposide, which produced a partial response. Tumor resection was performed, but margins were positive for PPB. Due to the high risk of recurrence, the authors elected to administrate high-dose chemotherapy using melphalan, etoposide, and carboplatin, followed by autologous HSCT. The patient achieved complete hematologic recovery, and reimaging after HSCT showed no evidence of disease. She relapsed 4 months later and died about 9 months after the completion of high-dose therapy. The role of high-dose chemotherapy and autologous HSCT is likely to be limited in PPB.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Marine-derived anticancer agents in clinical trials.

Anticancer agents may be derived either from the isolation of an active lead compound occurring spontaneously in nature or by novel chemical synthesis in the laboratory. There are examples of successful drugs being derived from both sources, which have had a profound impact on the natural history of various types of cancer. The treatment of lymphomas and acute leukaemias with the use of combination chemotherapy, including anthracyclines and vinca alkaloids, are examples of the contribution of nature. In contrast, agents such as 5-fluorouracil, methotrexate and more recently, the humanised anti-CD20 antibody rituximab and the tyrosine kinase inhibitor imatinib are examples of synthetic compounds, which were designed with a clear rationale, that are routinely used in patients with solid tumours and haematological malignancies. Until recently, the tradition in natural product-derived anticancer drug development was to rely almost exclusively on the screening of terrestrial sources (plant extracts and fermentation products) for their cytotoxic properties. Although C-nucleosides obtained from Caribbean sponge were the initial inspiration for the synthesis of antiviral substituted nucleosides and the successful anticancer agent citarabine, active against leukaemias and lymphomas, the contribution of marine compounds as a source of anticancer agents was modest. In recent years, the improvements in the technology of deep-sea collection and aquaculture added to the growing recognition of the tremendous biodiversity present in the marine world, and has contributed to the growing interest of exploring the oceans as a potential source of new anticancer candidates. This is reflected in the number of marine-derived compounds undergoing preclinical and early clinical development. In this paper, the authors discuss the available literature on anticancer agents that have reached clinical trials, such as didemnin B, aplidine, dolastatin-10, bryostatin-1 and ecteinascidin-743 (ET-743, trabectedin), as well as other promising compounds still undergoing tests in the laboratory.

Animals↗
PubMed2002

Comparative genotoxic effect of vincristine, vinblastine, and vinorelbine in somatic cells of Drosophila melanogaster.

In this study, the vinca alkaloids vincristine (VCR), vinblastine (VBL) and vinorelbine (VNR) were investigated for genotoxicity in the wing Somatic Mutation and Recombination Test (SMART) of Drosophila. Our in vivo experiments demonstrated that all drugs assessed induced genetic toxicity, causing increments in the incidence of mutational events, as well as in somatic recombination. Another point to be considered is the fact that VNR was able to induce, respectively, approximately 13.0 and 1.7 times more mutant clones per millimolar exposure unit as their analogues VCR and VBL. The replacement of a CH(3) attached to vindoline group in VBL by a CHO in VCR seems to be responsible for the approximately seven times higher potency of the former. In contrast, the structural modifications on VNR's catharantine group could be related to its higher genotoxic potency, as well as its similar mutagenic and recombinagenic action.

Animals↗
PubMed2002

Metastatic renal cell carcinoma involving the rectum.

BACKGROUND AND AIMS: Metastatic spread of a distant tumor to the rectum is extremely rare. To our knowledge, there have been no published reports of hematogenic metastasis from a renal cell carcinoma to the rectum. PATIENTS AND METHODS: A patient with a renal cell carcinoma was initially treated by a radical right nephrectomy. RESULTS: Nine months after the surgery he started to have multiple episodes of hematochezia. Colonoscopy showed a nodular lesion located in the distal rectum, and biopsy revealed an undifferentiated carcinoma. The patient then underwent abdominoperineal resection of the rectum, and histological examination showed metastatic renal clear cell carcinoma. CONCLUSION: This case represents an exceedingly rare condition, which has never been reported before.

Carcinoma, Renal Cell↗
PubMed2002

Von Willebrand factor in colorectal cancer.

BACKGROUND AND AIM: Von Willebrand factor (vWF) is a protein that mediates adherence of platelets to subendothelium during primary hemostasis. High vWF plasma concentrations have been reported in patients with various types of cancer, such as squamous cell carcinoma of the larynx and the cervix. This effect is associated with tumor-related angiogenesis and the metastatic process. The aim of this study was to determine plasma levels of vWF in a series of patients with colorectal carcinoma and the correlation of these values with specific prognostic predictors for the disease. PATIENTS AND METHODS: vWF was measured by quantitative immunoelectrophoresis in 75 patients with colorectal carcinoma at various Dukes' stages and compared with results from 88 healthy controls. RESULTS: Cancer patients had significantly higher vWF concentrations than controls. vWF plasma levels were associated with tumor staging, invasion of adjacent organs by the tumor, and presence of distant metastases. There was no significant correlation between vWF values and tumor size, histological grading, or plasma carcinoembryonic antigen levels. CONCLUSIONS: The levels of vWF are elevated in patients with colorectal cancer, and these values tend to increase with tumor progression. Considering that vWF is related to the process of tumor angiogenesis and may contribute to metastatic dissemination of malignant cells, further studies of its potential role as a marker of tumor progression in patients with colorectal cancer are warranted. It should be pointed out, however, that these observations need to be substantiated with additional studies using other methods and, preferably, the determination of vWF levels synthesized in the tumor tissues.

Case-Control Studies↗
PubMed2002

Phase II trial of cisplatin plus decitabine, a new DNA hypomethylating agent, in patients with advanced squamous cell carcinoma of the cervix.

On the basis of the demonstrated single-agent activity of cisplatin in patients with advanced cervical cancer and the observation of in vitro synergism between this agent and decitabine, a new DNA hypomethylating agent, we designed a phase II trial in which the combined use of the two agents are used as first-line therapy in patients with recurrent and/or metastatic disease. Eligible patients were those with histopathologically proven diagnosis of squamous cell carcinoma of the cervix, which was not considered suitable for curative surgery and/or irradiation, having measurable disease, leukocyte counts more than or equal to 4,000/microl, thrombocyte counts more than or equal to 100,000/microl, serum creatinine more than or equal to 1.5 mg/dl, and normal liver function tests. Initial dose of cisplatin was 40 mg/m(2), whereas decitabine was 50 mg/m(2) for 3 consecutive days every 21 days. Because of toxicity, the dose of cisplatin was reduced to 30 mg/m(2). Twenty-five patients were included in the study; 24 of them were eligible for the evaluation of toxicity, whereas 21 of them were eligible for the evaluation of tumor responses. Nineteen (79.2%) patients had received prior radiotherapy. A total of 75 cycles of chemotherapy were administered to the patients, with a median of 3 cycles (range: 1-8) per patient. The most frequently observed side effect was neutropenia, which was National Cancer Institute- Common Toxicity Criteria grades III and IV in 68.0% of cases. One patient died of complications caused by drug-related neutropenic sepsis. The most common nonhematologic grades III and IV toxicities were nausea and vomiting, which occurred in 17.3% and 9.3% of the cycles, respectively. Of a total of 21 patients evaluable for tumor response, 8 (38.1%) achieved a partial response, whereas stable disease was documented in 5 cases (23.8%). Median progression-free interval (PFI) was 16 weeks, and median survival was 19 weeks (95% CI 7.9-31.2). Objective responses were more frequent in patients with metastatic lesions in nonirradiated sites. Cisplatin- decitabine combination was moderately active in patients with advanced squamous cell carcinoma of the cervix, mainly in patients presenting with metastatic disease at previously nonirradiated sites. However, this regimen produced significant hematologic toxicity. Further studies with this combination including a larger patient population, preferably with the concomitant administration of hematopoietic growth factors, are warranted.

Adult↗