Cancer chemotherapy and cognitive function in rodent models: memory impairment induced by cyclophosphamide in mice.
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Animals↗
Biomedical subjects
Gilberto Schwartsmann
Publications and source records attributed to Gilberto Schwartsmann.
Systemic treatment of AIDS-related Kaposi sarcoma: current status and perspectives.
Kaposi's sarcoma (KS) is the most frequent type of cancer in patients with Acquired Immune Deficiency Syndrome (AIDS). In the western world, its incidence decreased dramatically in the era of highly active anti-retroviral therapy (HAART). In contrast, the incidence of KS has been steadily climbing in parallel with the AIDS epidemic in Africa over the past 10-15 years, being the most common cancer in adult men in countries like Uganda and Zimbabwe. AIDS-KS can be diagnosed at any stage of HIV infection, although it more commonly occurs in the setting of severe immune suppression, especially with an elevated viral load. Up to now, AIDS-KS is still an incurable disease. Its clinical course is variable, ranging from very indolent cases, requiring no or minimal therapy, to a rapidly progressive disease. Various local therapies are available to control small and asymptomatic lesions, while cytotoxic, immunological and biological therapies can be considered for more aggressive disease. The primary goal of therapy in most of the cases is to provide safe and effective palliation, in order to quality of life. Optimal anti-retroviral therapy is a key component of AIDS-KS management. There are still many questions to be answered in the management of patients with AIDS-KS, such as (1) What are the therapeutic agents that should be used in this disease, and in which sequence? and (2) What are the benefits and risks expected with each treatment option? The aim of this review is to discuss the systemic management of AIDS-KS, with special focus on the above mentioned questions.
Acquired Immunodeficiency Syndrome↗
A role for hippocampal gastrin-releasing peptide receptors in extinction of aversive memory.
Although the gastrin-releasing peptide receptor has been implicated in memory consolidation, previous studies have not examined whether it is involved in extinction. Here we show that gastrin-releasing peptide receptor blockade in the hippocampus disrupts extinction of aversive memory. Male rats were trained in inhibitory avoidance conditioning and then returned repeatedly to the training context without shock on a daily basis for 3 days. Infusion of a gastrin-releasing peptide receptor antagonist or the protein synthesis inhibitor anisomycin into the dorsal hippocampus immediately after the first extinction session blocked extinction. These drugs did not affect performance in subsequent sessions when the first extinction session (1 day after training) was omitted. The results indicate that hippocampal gastrin-releasing peptide receptors are involved in memory extinction.
Animals↗
Disparities in cancer care: a worldwide perspective and roadmap for change.
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Global Health↗
Opposite effects of low and high doses of the gastrin-releasing peptide receptor antagonist RC-3095 on memory consolidation in the hippocampus: possible involvement of the GABAergic system.
Although the gastrin-releasing peptide receptor (GRPR) has recently emerged as a system importantly involved in regulating memory formation, the role of hippocampal GRPRs in memory remains controversial. The present study examined the effects of GRPR antagonism on memory consolidation in area CA1 of the hippocampus. Male Wistar rats received bilateral infusions of the GRPR antagonist [D-Tpi6, Leu13 psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095; 1, 3, or 10 microg/side) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. RC-3095 at 1 microg impaired, whereas the dose of 10 microg enhanced, 24-h IA retention. A second experiment showed that the RC-3095-induced enhancement of memory consolidation was prevented by pretraining infusion of an otherwise ineffective dose of the gamma-aminobutyric acid type A (GABA(A)) receptor agonist muscimol. The results indicate that high doses of GRPR antagonists can induce enhancement of memory consolidation in the hippocampus. In addition, the memory-enhancing effect of GRPR antagonists might be mediated by inhibition of GABAergic transmission.
Animals↗
Developing anticancer agents from natural sources.
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Antineoplastic Agents, Phytogenic↗
Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis.
RATIONALE: Several new therapeutic strategies have been described for the treatment of sepsis, but to date none are related to alterations in the bombesin/gastrin-releasing peptide (GRP) receptor pathways. OBJECTIVES: To determine the effects of a selective GRP receptor antagonist, RC-3095, on cytokine release from macrophages and its in vivo effects in the cecal ligation and puncture (CLP) model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. METHODS: We determined the effects of RC-3095 in the CLP model of sepsis and in acute lung injury induced by intratracheal instillation of LPS. In addition, we determined the effects of RC-3095 on tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, and nitric oxide release from activated macrophages. MEASUREMENTS AND MAIN RESULTS: The GRP antagonist attenuated LPS- or CLP-induced TNF-alpha, IL-1beta, and nitric oxide release in cultured macrophages and decreased the mRNA levels of inducible nitric oxide synthase. The administration of RC-3095 (0.3 mg/kg) 6 h after sepsis induction improved survival in the CLP model, and diminished lung damage after intratracheal instillation of LPS. These effects were associated with attenuation on the circulating TNF-alpha and IL-1beta levels and decreased myeloperoxidase activity in several organs. CONCLUSIONS: We report that a selective GRP receptor antagonist attenuates the release of proinflammatory cytokines in vitro and in vivo and improves survival in "established" sepsis. These are consistent with the involvement of a new inflammatory pathway relevant to the development of sepsis.
Animals↗
Non-associative learning and anxiety in rats treated with a single systemic administration of the gastrin-releasing peptide receptor antagonist RC-3095.
The gastrin-releasing peptide receptor (GRPR) has been implicated in the modulation of emotionally-motivated memory. In the present study, we investigated the role of the GRPR on non-emotional, non-associative memory, and anxiety. Adult male Wistar rats were given a systemic injection of the GRPR antagonist [D-Tpi6, Leu(13) psi(CH2NH)-Leu14] bombesin (6-14) (RC-3095) (0.2, 1.0 or 5.0mg/kg) 30 min before exposure to an open field or an elevated plus maze. Habituation to the open field was tested in a retention trial carried out 24 h after the first exposure to the open field. Rats given RC-3095 at the doses of 1.0 or 5.0mg/kg showed impaired habituation. Animals treated with 5.0mg/kg of RC-3095 spent significantly more time in the closed arms of the elevated plus maze. No effects of RC-3095 on locomotion or exploratory behavior were observed. The results implicate the GRPR in the regulation of non-emotional, non-associative memory as well as in anxiety.
Animals↗
Low cytotoxicity of ecteinascidin 743 in yeast lacking the major endonucleolytic enzymes of base and nucleotide excision repair pathways.
Ecteinascidin 743 (ET-743) is a promising antitumoral drug for the treatment of soft tissues sarcomas, becoming a good candidate for clinical trials. However, the molecular mechanism of how ET-743 induces cells death is poorly understood. The chemical structure of ET-743 suggests that it can form cytotoxic cross-links with proteins and DNA. Experiments with Escherichia coli and mammalian cells indicate that the nucleotide excision repair (NER) pathway promotes ET-743 cytotoxicity. We therefore analyzed cytotoxicity and tolerance to ET-743 in the yeast Saccharomyces cerevisiae, defective for NER and/or base excision repair (BER), either in single mutants or in combination with mutant alleles of genes encoding proteins involved in DNA translesion synthesis (TLS) and homologous recombination (HR). Treatment of haploid and diploid S. cerevisiae strains with ET-743 led to induced mutagenesis, mitotic gene conversion, and crossing-over. The results indicated that yeast strains lacking endonucleases of the NER and BER pathways are especially resistant for ET-743. The mutagenesis data points to a weak mutagenic activity of ET-743 in both WT and strains lacking BER/NER endonuclease, and that a mutant blocked in both BER and TLS totally lacks induced mutagenesis. The diploid strain shows an increase in the frequencies of crossing-over and mitotic recombination. These data lead us to propose a model for ET-743 action in eukaryotic cells, where the presence of BER and NER endonucleases results in cell death. However, ET-743 damage can be tolerated in BER and/or NER mutants by TLS (error-prone) or in combination with HR (error-free).
Antineoplastic Agents↗
The irinotecan/5-fluorouracil combination induces apoptosis and enhances manganese superoxide dismutase activity in HT-29 human colon carcinoma cells.
BACKGROUND: We examined whether induction of apoptosis and Mn-superoxide dismutase (Mn-SOD) and Cu,Zn-superoxide dismutase (Cu,Zn-SOD) activities were involved in the greater cytotoxicity of the irinotecan (CPT-11)/5-fluorouracil (5-FU) combination for human colon cancer cells when compared to both drugs alone. METHODS: HT-29 and SNU-C4 human colon carcinoma cell lines were treated with 5-FU and CPT-11, then apoptosis was evaluated by flow cytometry and SOD activities were determined by polyacrylamide gel electrophoresis. RESULTS: Enhanced apoptosis of HT-29 cells was observed with all treatments containing 5-FU in SNU-C4 cells; however, in HT-29 cells, apoptosis was enhanced only with the CPT-11/5-FU combination. In the SNU-C4 cell line, none of the treatments exerted a significant effect on Cu,Zn-SOD or Mn-SOD activity. However, in HT-29 cells, the CPT-11/5-FU combination enhanced Mn-SOD activity when compared to cells treated with CPT-11 alone. Nevertheless, the combined treatment did not interfere with Cu,Zn-SOD activity. CONCLUSION: Treatment with the CPT-11/5-FU combination may promote in HT-29 cell apoptosis by enhancing Mn-SOD activity.
Antineoplastic Agents↗
Quantification of the bombesin/gastrin releasing peptide antagonist RC-3095 by liquid chromatography-tandem mass spectrometry.
Bombesin (BN) and its mammalian equivalent, gastrin-releasing peptide (GRP), stimulate cell proliferation and are involved in the pathogenesis of several types of human cancer. BN/GRP and their receptors were shown to be critical for the growth of various human malignancies, such as small-cell lung, prostate, ovary, stomach and breast cancers in the human tumor xenograft model. In the present study, a fast, sensitive, robust method was developed for the determination and quantification of a BN/GRP receptor antagonist RC-3095 (D-Tpi-Gln-Trp-Ala-Val-Gly-His-Leupsi(CH2NH)Leu-NH2), in human plasma by liquid chromatography coupled with tandem mass spectrometry. RC-3095 was extracted from 0.2 ml human plasma by protein precipitation using cold acetonitrile (0.4 ml). The method has a chromatographic run of 10 min using a C(8) analytical column (150 mm x 4.6 mm i.d.) and the linear calibration curve over the range was linear from 20 to 10000 ng ml(-1) (r(2)>0.994). The between-run precision, based on the relative standard deviation replicate quality controls, was 5.7% (60 ng ml(-1)), 7.1% (600 ng ml(-1)) and 6.8% (8000 ng ml(-1)). The between-run accuracy was +/-0.0, 2.1 and 3.1% for the above-mentioned concentrations, respectively. The developed procedure allows the quantitative determination of peptide RC-3095 for pharmacokinetics studies in human plasma.
Bombesin↗
Dexamethasone reverses the memory impairment induced by antagonism of hippocampal gastrin-releasing peptide receptors.
Storage of emotionally influenced memory is regulated by activation of glucocorticoid receptors (GRs) as well as of gastrin-releasing peptide receptors (GRPRs) in the dorsal hippocampus. In the present study, male Wistar rats were given a bilateral infusion of saline or the GRPR antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) (1.0 microg/side) into the dorsal hippocampus 10 min before training on an inhibitory avoidance task, followed by an immediate post-training i.p. injection of vehicle or the GR agonist dexamethasone (0.3 mg/kg). A retention test trial, carried out 24 h after training, indicated that intrahippocampal infusion of RC-3095 impaired inhibitory avoidance retention. Post-training administration of dexamethasone induced an enhancement of retention regardless of whether the animals had received saline or RC-3095 into the hippocampus before training. The findings indicate that hippocampal GRPR blockade does not prevent memory enhancement induced by dexamethasone. Together with previous results, these findings suggest that endogenous activation of GRPRs in the hippocampus modulates the consolidation of emotional memory, but is not a critical receptor system mediating memory formation.
Animals↗
Effects of toxic doses of glutamate on Cu-Zn and Mn/superoxide dismutases activities in human glioma cell lines.
Recent research has implicated glutamate in the growth and invasive migration of gliomas. Superoxide dismutase (SOD) is involved in excitotoxicity and may influence cellular proliferative status. Thus, this study investigated the effects of gliotoxic doses of glutamate on Cu-Zn and Mn/SODs activities in human glioma cell lines. To this end, glioma cell lines (U87MG, U138MG and U251MG) were treated with glutamate (5-200 mM) during 48 h. Then, cell viability assays, clonogenic assay and Cu-Zn and Mn/SODs activities of the cell lines were performed. IC50values of glutamate were similar for both U87MG and U138MG cells (56 and 69 mM, respectively), while a higher value was detected for U251MG cells (110 mM). In the long term, 14 days after glutamate was removed from the culture media, cells showed partial or complete recovery. The effects of glutamate treatment on Cu-Zn and Mn/SODs activities varied among the distinct cell lines. While acute treatment with toxic doses of glutamate caused a significant decrease in the Cu-Zn/SOD activity of U138MG and U251MG cells, it did not affect Cu-Zn/SOD activity in U87MG cells. Only in U251MG cells, acute glutamate treatment decreased significantly Mn/SOD activity. In the long term (14 days after the 48 h treatment), glutamate did not affect either Cu-Zn or Mn/SODs activities. Thus, it may be suggested that SOD vulnerability to glutamate-mediated effects may be related to distinct tumoral cell behavior.
Analysis of Variance↗
Antitumor activity of three benzopyrans isolated from Hypericum polyanthemum.
In the present study we have investigated the in vitro antitumor effects of three benzopyrans, 6-isobutyryl-5,7-dimethoxy-2,2-dimethylbenzopyran (1), 7-hydroxy-6-isobutyryl-5-methoxy-2,2-dimethylbenzopyran (2) and 5-hydroxy-6-isobutyryl-7-methoxy-2,2-dimethylbenzopyran (3) isolated from Hypericum polyanthemum. The three compounds tested demonstrated potent growth inhibitory activity at 40 microg/ml (<25% control growth) in the NCI-H460, HT-29 and U-373MG human cell lines. Determination of cell cycle distribution demonstrated that the antiproliferative effect of the three benzopyrans could be associated to alterations in the cell cycle phase distribution. Treatment with the IC50 of the three compounds induced an arrested in S phase. Only in cells treated with compound 3 did the percentage of sub-G1 population increase up to 9%, suggesting that this compound induced more cell death than the others. Consistent with sub-G1 analysis, appreciable oligonucleosomal DNA fragmentation was only observed in the NCI-H460 cell line treated with compound 3. From these results it can be suggested that despite no differences among the cytotoxicity of the three compounds, it was observed that the mechanism of their antiproliferative effects appears to be different.
Antineoplastic Agents, Phytogenic↗
MAPK pathway activation in colorectal cancer: a therapeutic opportunity for GRP receptor antagonists.
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Animals↗
Serum Hsp70 as an early predictor of fatal outcome after severe traumatic brain injury in males.
Severe traumatic brain injury (TBI) is associated with a 35-70% mortality rate. Biochemical markers of cellular stress/injury have been proposed to indicate outcome after head injury. Therefore, our aim was to determine whether Hsp70 could be detected in the serum of patients after severe TBI and whether serum levels of Hsp70 correlate with primary outcome in severe TBI. Twenty consecutive male patients, victims of severe TBI (GCS 3-8), were enrolled in this prospective study. Clinical outcome variables of severe TBI comprised: survival, time for ICU discharge, and neurological assessment using the Glasgow Outcome Scale (GOS) at the ICU discharge. Venous blood samples were taken at admission in the ICU (study entry), 24 h later, and 7 days later. A control group consisting of eight healthy male volunteers was also included. Serum Hsp70 levels were measured by an enzyme-linked immunosorbent assay. Mean serum Hsp70 concentrations were significantly increased in the TBI (97.6, 48.1, and 39.2 ng/mL, at study entry, 24 h later, and 7 days later, respectively) compared with the control group (12.2 ng/mL). Severe TBI was associated with a 50% mortality rate. On study entry (mean time 10.8 h after injury), a higher proportion of patients with fatal outcome had elevated serum Hsp70 (mean 143.5 ng/mL) concentrations when compared with survivors (mean 51.6 ng/mL). There was a significant correlation between higher initial serum Hsp70 concentrations and fatal outcome. The sensitivity of serum Hsp70 predicting mortality according to the cutoff of 62 ng/mL is 70% within 20 h after injury. Increased serum Hsp70 levels may constitute an early predictor of unfavorable outcome in severe TBI in males.
APACHE↗
Irinotecan/5-fluorouracil combination induces alterations in mitochondrial membrane potential and caspases on colon cancer cell lines.
The combination of irinotecan (CPT-11) and 5-fluorouracil (5-FU) is currently used in the treatment of advanced colorectal carcinoma. When compared to both agents alone, CPT-11 followed by 5-FU treatment demonstrated a synergistic effect. This observation can be related to increased in apoptosis induction after caspase activation. Several studies have demonstrated that changes in mitochondrial membrane potential occur earlier in apoptosis. In this study, we verified whether the collapse in mitochondrial membrane and the activation of caspases is responsible for increased apoptosis observed with CPT-11/5-FU treatment. Thus, HT-29 and SNU-C4 human colon carcinoma cell lines were exposed for 24 h to each drug alone, and to various combinations and treatment sequences, and assessed for colony formation, changes in the mitochondrial membrane potential, and the activities of caspase-3, -8, and -9. The CPT-11/5-FU treatment induced apoptosis in both cell lines; however, the most pronounced effect was observed in HT-29 cells. In these cells, both caspase-3 and -9 were involved in the activation of apoptosis after CPT-11/5-FU treatment. Moreover, in these cells, a reduction of 50% in mitochondrial membrane potential was observed with this treatment. On the other hand, in the SNU-C4 cell line in addition to caspase-3 and-9, caspase-8 seems to be important to apoptosis after CPT-11/5-FU treatment. Furthermore, in this cell line we did not observe alterations in mitochondrial membrane potential. In spite of the differences among the cell lines, these results indicated that the increase in apoptosis in HT-29 cells observed with CPT-11 followed by 5-FU treatment could be explained by a disruption in mitochondria membrane potential that induced caspases activation.
Antimetabolites, Antineoplastic↗
RC-3095, a bombesin/gastrin-releasing peptide receptor antagonist, impairs aversive but not recognition memory in rats.
Bombesin and its mammalian equivalent, gastrin-releasing peptide (GRP), stimulate cell proliferation and are involved in the pathogenesis of several types of human cancer. Bombesin-like peptides also display neuroendocrine activities and regulate neural function. In the present study, we evaluated the effects of the bombesin/GRP receptor antagonist (D-Tpi(6), Leu(13) psi[CH(2)NH]-Leu(14)) bombesin-(6-14) (RC-3095), experimental antitumor drug, on memory in rats. Adult female Wistar rats were treated with an intraperitoneal injection of RC-3095 (0.2, 1.0 or 5.0 mg/kg) 30 min before training in either inhibitory avoidance or novel object recognition tasks. Retention test trials were carried out 1.5 (short-term memory) or 24 h (long-term memory) after training. RC-3095 at the doses of 0.2 or 1.0 mg/kg, but not at the dose of 5.0 mg/kg, impaired both short- and long-term inhibitory avoidance retention, but did not affect recognition memory. The memory-impairing effect of RC-3095 could not be attributed to alterations in sensorimotor functions. The results show that the antitumor drug/GRP antagonist RC-3095 impairs formation of aversive memory.
Animals↗