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Background: We examined the impact of polypharmacy on the quality of the anticoagulation therapy in patients with atrial fibrillation. We also examined the factors that affect the stability of warfarin therapy. Methods and Results: This retrospective study was conducted using data from 157 consecutive outpatients with atrial fibrillation in a single tertiary referral hospital. Patients who were prescribed warfarin continuously and for whom PT-INR was examined at least three times in a year were included in this study. We examined the quality of warfarin therapy using time in the therapeutic INR range (TTR), percentage of PT-INR determinations in range (PINRR), and the coefficient variation (CV) of PT-INR. We found that the number of prescribed medicines was significantly associated with high BMI and low eGFR, but not with TTR, PINRR, and the coefficient variation of PT-INR in patients with atrial fibrillation. We also found that female gender was independently associated with low PINRR in this study population. Conclusion: Polypharmacy did not deteriorate the quality of warfarin therapy in patients with atrial fibrillation treated in the tertiary referral hospital. Female gender was an independent predictor of the low quality of warfarin therapy.
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BACKGROUND: Polypharmacy is associated with poor prognosis of patients with various diseases. However, it has not been precisely addressed how polypharmacy affects the clinical characteristics of the cardiovascular outpatients. The aim of this study is to search for the clinical characteristics related to the number of prescribed drugs in the cardiovascular outpatients. Also, we examine whether the number of the prescribed drugs affects the worsening of renal function. METHODS: This retrospective study was conducted using the data of 259 continuous cardiovascular outpatients who were examined complete blood count (CBC) and serum creatinine. RESULTS: In the univariate analysis, the number of prescribed drugs were associated with the number of cardiovascular diseases or their risk factors, age, white blood cells, platelet, body mass index, anemia, and chronic kidney disease stage 3b or higher. In the multivariable analysis, independent variables that significantly correlated with the number of prescribed drugs were the number of cardiovascular diseases or their risk factors, anemia, and chronic kidney disease stage 3b or higher. Among 259 patients, 208 patients received follow-up examination of serum creatinine. The number of prescribed drugs was the only factor that was associated with accelerated deterioration of renal function. CONCLUSIONS: Polypharmacy is associated not only with poor renal function but with accelerated deterioration of renal function. Polypharmacy may be causally related with renal dysfunction.
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BACKGROUND AND PURPOSE: Neuromedin U (NmU) may be a novel target for obesity treatment owing to its anorectic and energy expenditure enhancing effects. Although two receptors, NMU1 and NMU2, are both responsible for the NmU-mediated anti-obesity effects, the receptor agonist with the most appropriate profiles for treating obesity and diabetes in terms of efficacy and safety is as yet unknown. Thus, we developed and evaluated novel NMU1/2 receptor-selective agonists. EXPERIMENTAL APPROACH: Efficacy and safety were assessed in mice with diet-induced obesity (DIO) and those with leptin-deficient diabetes (ob/ob) through repeated peripheral administration of selective agonists to NMU1 (NMU-6102) and NMU2 (NMU-2084), along with non-selective NMU1/2 agonists (NMU-0002 and NMU-6014). We also performed immunohistochemistry for c-Fos protein expression in the brain to probe their mechanisms of action. KEY RESULTS: Although both non-selective NMU1/2 agonists and the NMU2-selective agonist had high efficacy compared with the NMU1-selective agonist, only the NMU2-selective agonist led to relatively low adverse effects, such as diarrhoea, in DIO mice. However, the non-selective NMU1/2 agonist and the NMU1-selective agonist, but not the NMU2-selective agonist, were effective in diabetic ob/ob mice. Mechanistically, NMU2-selective agonists preferentially activate pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus but not in the paraventricular nucleus. CONCLUSIONS AND IMPLICATIONS: These results suggest that an NMU2 receptor-selective agonist may be a well-balanced drug for the treatment of obesity and that an NMU1 receptor-selective agonist may also be beneficial for treating obesity and diabetes once its side effects are minimized.
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Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Oligopeptídeos/uso terapêutico , Receptores de Neurotransmissores/agonistas , Animais , Núcleo Arqueado do Hipotálamo/fisiologia , Encéfalo/metabolismo , Masculino , Camundongos , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.
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Desenho de Fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Aminas/química , Aminas/metabolismo , Aminas/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Ligação Proteica , Mapas de Interação de Proteínas , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Técnicas do Sistema de Duplo-HíbridoRESUMO
The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure revealed that the peptide binds near Switch II and allosterically blocks protein-protein interactions with the guanine nucleotide exchange factor. This discovery of a unique binding pocket provides valuable information that will facilitate the design of direct Ras inhibitors.
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Cytidine triphosphate synthase 1 (CTPS1) is an enzyme expressed in activated lymphocytes that catalyzes the conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP) with ATP-dependent amination, using either L-glutamine or ammonia as the nitrogen source. Since CTP plays an important role in DNA/RNA synthesis, phospholipid synthesis, and protein sialyation, CTPS1-inhibition is expected to control lymphocyte proliferation and size expansion in inflammatory diseases. In contrast, CTPS2, an isozyme of CTPS1 possessing 74% amino acid sequence homology, is expressed in normal lymphocytes. Thus, CTPS1-selective inhibition is important to avoid undesirable side effects. Here, we report the discovery of CTpep-3: Ac-FRLGLLKAFRRLF-OH from random peptide libraries displayed on T7 phage, which exhibited CTPS1-selective binding with a KD value of 210nM in SPR analysis and CTPS1-selective inhibition with an IC50 value of 110nM in the enzyme assay. Furthermore, two fundamentally different approaches, enzyme inhibition assay and HDX-MS, provided the same conclusion that CTpep-3 acts by binding to the amidoligase (ALase) domain on CTPS1. To our knowledge, CTpep-3 is the first CTPS1-selective inhibitor.
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Bacteriófago T7/metabolismo , Carbono-Nitrogênio Ligases/antagonistas & inibidores , Linfócitos/enzimologia , Peptídeos/farmacologia , Humanos , Linfócitos/efeitos dos fármacos , Biblioteca de PeptídeosRESUMO
Keap1 constitutively binds to the transcription factor Nrf2 to promote its degradation, resulting in negative modulation of genes involved in cellular protection against oxidative stress. Keap1 is increasingly recognized as an attractive target for treating diseases involving oxidative stress, including cancer, atherosclerosis, diabetes, arthritis, and neurodegeneration. We used phage-display peptide screening to identify a tetrapeptide showing moderate binding affinity, which inhibits the interaction between Nrf2 and Keap1. The tetrapeptide does not include an ETGE motif, which is a commonly found consensus sequence in known peptidic inhibitors. In addition to affinity parameters, IC50, KD, and thermodynamic parameters, the crystal structure of the complex was determined to elucidate the binding conformation. The binding interactions resemble those of known small-molecule inhibitors as opposed to those of substrates and peptidic inhibitors. Although the tetrapeptide's affinity is not very high, our results may help facilitate the designing of small-molecule inhibitors during lead generation in drug discovery.
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Proteína 1 Associada a ECH Semelhante a Kelch/química , Fator 2 Relacionado a NF-E2/química , Oligopeptídeos/química , Motivos de Aminoácidos , Sítios de Ligação , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/antagonistas & inibidores , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Cinética , Modelos Moleculares , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Oligopeptídeos/síntese química , Biblioteca de Peptídeos , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , TermodinâmicaRESUMO
Amino-acid mutations of Gly12 (e.g. G12D, G12V, G12C) of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras), the most promising drug target in cancer therapy, are major growth drivers in various cancers. Although over 30 years have passed since the discovery of these mutations in most cancer patients, effective mutated K-Ras inhibitors have not been marketed. Here, we report novel and selective inhibitory peptides to K-Ras(G12D). We screened random peptide libraries displayed on T7 phage against purified recombinant K-Ras(G12D), with thorough subtraction of phages bound to wild-type K-Ras, and obtained KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2) as a consensus sequence. KRpep-2 showed more than 10-fold binding- and inhibition-selectivity to K-Ras(G12D), both in SPR analysis and GDP/GTP exchange enzyme assay. KD and IC50 values were 51 and 8.9 nM, respectively. After subsequent sequence optimization, we successfully generated KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2) that inhibited enzyme activity of K-Ras(G12D) with IC50 = 1.6 nM and significantly suppressed ERK-phosphorylation, downstream of K-Ras(G12D), along with A427 cancer cell proliferation at 30 µM peptide concentration. To our knowledge, this is the first report of a K-Ras(G12D)-selective inhibitor, contributing to the development and study of K-Ras(G12D)-targeting drugs.
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Descoberta de Drogas/métodos , Neoplasias Experimentais/tratamento farmacológico , Biblioteca de Peptídeos , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/química , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Bacteriófago T7 , Sítios de Ligação , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Humanos , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteases/metabolismo , Ligação Proteica , Mapeamento de Interação de Proteínas/métodos , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
Dedicator of cytokinesis 2 (DOCK2) is a key molecule for lymphocyte activation and migration. DOCK2 interacts with Ras-related C3 botulinus toxin substrate 1 (Rac1, GTPase) and mediates the GDP-GTP exchange reaction, indicating that inhibitors against protein-protein interaction (PPI) between DOCK2 and Rac1 would be good drug candidates for treating immune-related disorders. Here, we report DOCK2-selective PPI inhibitory peptides discovered using random peptide T7 phage display technology. These peptides inhibited DOCK2 activity at nanomolar concentrations and were delivered to intracellular compartments by combination with cell-penetrating peptide (CPP). Consequently, one peptide, R4-DCpep-2(V2W/K4R/ox)-NH2 (Ac-RRRRCWARYHGYPWCRRRR-NH2), inhibited migration in human B lymphocyte MINO cell line at IC50 = 120 nM. To our knowledge, this is the first report of a DOCK2-selective peptide inhibitor; this study will contribute to the development of novel DOCK2-targeting immunosuppressive drugs.
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Fatores de Troca do Nucleotídeo Guanina/antagonistas & inibidores , Linfoma de Células B/tratamento farmacológico , Peptídeos/química , Peptídeos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sistema Livre de Células , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas Ativadoras de GTPase , Humanos , Linfoma de Células B/patologia , Biblioteca de Peptídeos , Peptídeos/metabolismo , Mapas de Interação de Proteínas , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
The phospholipid hydroperoxidase glutathione peroxidase (GPX4) is an enzyme that reduces lipid hydroperoxides in lipid membranes. Recently, GPX4 has been investigated as a target molecule that induces iron-dependent cell death (ferroptosis) selectively in cancer cells that express mutant Ras. GPX4 inhibitors have the potential to become novel anti-cancer drugs. However, there are no druggable pockets for conventional small molecules on the molecular surface of GPX4. To generate GPX4 inhibitors, we examined the use of peptides as an alternative to small molecules. By screening peptide libraries displayed on T7 phages, and analyzing the X-ray crystal structures of the peptides, we successfully identified one peptide that binds to near Sec73 of catalytic site and two peptides that bind to another site on GPX4. To our knowledge, this is the first study reporting GPX4 inhibitory peptides and their structural information.
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Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , Glutationa Peroxidase/antagonistas & inibidores , Biblioteca de Peptídeos , Peptídeos/química , Bacteriófago T7/genética , Sítios de Ligação , Ativação Enzimática , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Ligação Proteica , Conformação ProteicaRESUMO
B cell lymphoma 6 (BCL6) is a transcriptional repressor that interacts with its corepressors BcoR and SMRT. Since this protein-protein interaction (PPI) induces activation and differentiation of B lymphocytes, BCL6 has been an attractive drug target for potential autoimmune disease treatments. Here we report a novel BCL6 inhibitory peptide, F1324 (Ac-LWYTDIRMSWRVP-OH), which we discovered using phage display technology; we also discuss this peptide's structure-activity relationship (SAR). For BCL6(5-129) binding, KD and IC50 values of F1324 were 0.57 nM and 1 nM according to the results of an SPR analysis and cell-free ELISA assay, respectively. In contrast, BcoR(Arg498-514Pro) and SMRT(Leu1422-Arg1438) exhibited relatively weak micromole-order binding to BCL6. Furthermore, Fusion protein AcGFP-F1324 transiently expressed in HEK293T cells inhibited intracellular PPI in cell-based M2H assay. By examination of the truncation and fragmentation of F1324, the C-terminal sequence WRVP, which is similar to the BcoR(509-512) sequence WVVP, was identified as being critical for BCL6 binding. In addition, subsequent single-crystal X-ray diffraction analysis of F1324/BCL6(5-129) complex revealed that the high affinity of F1324 was caused by effective interaction of its side chains while its main chain structure was similar to that of BcoR(Arg498-514Pro). To our knowledge, F1324 is the strongest BCL6-binding peptide yet reported.
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Inibidores Enzimáticos/química , Peptídeos/química , Proteínas Proto-Oncogênicas c-bcl-6/química , Proteínas Proto-Oncogênicas c-bcl-6/ultraestrutura , Sítios de Ligação , Ativação Enzimática , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
UNLABELLED: Retrospective studies have suggested that UDP-glucuronosyltransferase (UGT)1A1, UGT1A7, and UGT1A9 predict severe toxicity and efficacy of irinotecan-containing regimens. We prospectively evaluated the impact of UGT1A genotypes and haplotypes on severe toxicity and efficacy in patients treated with fluorouracil, leucovorin, and irinotecan combination chemotherapy (FOLFIRI) for metastatic colorectal cancer (mCRC) from the two prospective multicenter phase II studies in Japan. The FLIGHT1 study was a first-line FOLFIRI trial, and FLIGHT2 was a FOLFOX-refractory, second-line FOLFIRI trial. A total of 73 patients agreed to additional analysis, and were genotyped for UGT1A polymorphisms, UGT1A1*28 (TA6>TA7), UGT1A1*6 (211G>A), UGT1A1*27 (686C>A), UGT1A1*60 (-3279T>G), UGT1A1*93 (-3156G>A), UGT1A7 (-57T>G), UGT1A7*3 (387T>G, 622T>C), and UGT1A9*22 (T9>T10). Of 73 patients, 34 developed G3/4 severe hematological toxicities. The toxicities were significantly more frequent in patients with UGT1A1*6 (211A), UGT1A7 (387G), and UGT1A9*22 reference alleles (T9). Haplotype I, which consists of all favorable alleles, was associated with a significant reduction in hematologic toxicity (P = 0.031). In contrast, haplotype II, which contains four high-risk alleles, showed significantly higher hematologic toxicity than the other haplotypes (P = 0.010). Six out of seven patients who were homozygous for UGT1A1*28 or *6 experienced severe hematological toxicity despite the fact that their response rate was not impaired (42.9%). We concluded that UGT1A polymorphisms, especially UGT1A1*6, are important for the prediction of severe toxicity of FOLFIRI in northeast Asian populations. In this regard, haplotype analyses should substantially impact the prediction of severe hematological toxicities of FOLFIRI. ( CLINICAL TRIAL REGISTRATION: UMIN000002388 and UMIN000002476).
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Glucuronosiltransferase/genética , Neutropenia/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Neoplasias Colorretais/genética , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Frequência do Gene , Genótipo , Haplótipos/genética , Humanos , Irinotecano , Japão , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neutropenia/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , UDP-Glucuronosiltransferase 1ARESUMO
BACKGROUND: On the basis of international clinical trials, capecitabine plus cisplatin (XP) as a first-line treatment of advanced gastric cancer is considered a global standard regimen. However, the usefulness of XP as compared with S-1 plus cisplatin (SP), which is considered standard therapy in Japan, has not yet been assessed. METHODS/DESIGN: This is a multicenter randomized phase II trial to elucidate the efficacy of XP as compared with SP for first-line treatment of advanced gastric cancer. Patients with unresectable metastatic or recurrent gastric cancer, 20-74 years of age and human epidermal growth factor 2 (HER2)-negative status, will be assigned in a 1:1 ratio to receive either S-1 40 mg/m2 bid for 21 days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 (day 1) every 3-week cycle. Patients will be also asked to the analysis of tumor tissues for translational investigations. The Primary endpoint is progression-free survival and secondary endpoints are overall survival, time to treatment failure, tumor response rate and safety. These comparisons will also be evaluated in terms of biomarkers. Planned sample size is 100 (50 in each arm), which is appropriate for this trial. DISCUSSION: Fluoropyrimidine plus cisplatin combination is the standard regimen of the first line treatment for advanced gastric cancer. Both S-1 and capecitabine are the prodrug of 5-FU but differ from their process of metabolism. Result of this trial and translational research will provide the important clues to prepare the individualized therapy for advanced gastric cancer in the near future. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01406249.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adulto , Idoso , Capecitabina , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Combinação de Medicamentos , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagem , Adulto JovemRESUMO
OBJECTIVE: We evaluated DNA amplificability to achieve a 100% success rate in KRAS mutation testing with dideoxy sequencing using formalin-fixed and paraffin-embedded colorectal cancer tissue samples obtained from a recent clinical trial. METHODS: We evaluated the effects of deparaffinization, formalin fixation or storage time, and amplicon size on the amplificability of DNAs extracted from 19 formalin-fixed and paraffin-embedded colorectal cancer tissue samples. We subjected to KRAS mutation analysis 112 samples from metastatic colorectal cancer patients in 31 hospitals enrolled in a Phase II trial of a second-line FOLFIRI (5-fluorouracil+ leucovorin + irinotecan) + cetuximab regimen. RESULTS: Deparaffinization, formalin fixation and storage times did not appear to affect the recovery and amplificability of DNAs. However, amplicon size had a remarkable effect on the amplificability of DNAs. The smaller fragments with a size of ≤278 bp (96-278 bp) were successfully amplified with polymerase chain reaction in all samples tested, whereas the larger fragments with a size of ≥298 bp (298-565 bp) were not amplified. All samples from our clinical trial were successfully analyzed using three sets of primers with the amplicon sizes of 201, 221 and 240 bp, and KRAS mutations in exons 2 and 3 were detected in 49 of the 112 cases (43.8%). CONCLUSIONS: These data suggest that the evaluation of DNA amplificability and amplicon size is important for the success of mutation detection tests such as the KRAS test with dideoxy sequencing using formalin-fixed and paraffin-embedded tissue samples in the clinical setting.
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Neoplasias Colorretais/patologia , Análise Mutacional de DNA/métodos , Técnicas de Preparação Histocitológica , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Neoplasias Colorretais/genética , Fixadores , Formaldeído , Humanos , Inclusão em Parafina , Proteínas Proto-Oncogênicas p21(ras) , Fixação de TecidosRESUMO
BACKGROUND: The object of this study was to investigate the safety and clinical response of immunotherapy targeting the WT1 (Wilms' tumor 1) gene product in patients with gynecological cancer. PATIENTS AND METHODS: Twelve patients with WT1/human leukocyte antigen (HLA)-A*2402-positive gynecological cancer were included in a Phase II clinical trial of WT1 vaccine therapy. In all the patients, the tumors were resistant to standard therapy. The patients received intradermal injections of a HLA-A*2402-restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was measured by computed tomography (CT), was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: stable disease (SD) in 3 patients and progressive disease (PD) in 9 patients. No patients had a complete (CR) or partial response (PR). The disease control rate was 25.0%. CONCLUSION: Although a small, uncontrolled, nonrandomized trial, this study showed that WT1 vaccine therapy for patients with gynecological cancer was safe and produced a clinical response.
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Vacinas Anticâncer/uso terapêutico , Neoplasias dos Genitais Femininos/terapia , Proteínas WT1/imunologia , Adulto , Idoso , Feminino , Neoplasias dos Genitais Femininos/imunologia , Antígenos HLA-A/biossíntese , Antígenos HLA-A/imunologia , Antígeno HLA-A24 , Humanos , Injeções Intradérmicas , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologiaRESUMO
BACKGROUND AND AIMS: The efficacy of a biological response modifier polysaccharide K in adjuvant immunochemotherapy was evaluated in primary colon cancer patients with macroscopic Dukes' C after curative resection. PATIENTS AND METHODS: Employing the minimization method using three factors (lymph node metastases, preoperative serum CEA level, and institution), 446 patients were allocated into groups P and C. Group P received immunochemotherapy, oral PSK (3 g per day) followed by oral 5-FU (200 mg/body per day), while group C received only intermittent chemotherapy, oral 5-FU (200 mg per day) followed by 4-week rest. Both groups received ten courses. RESULTS: Survival for cancer death was significantly higher in group P than in group C, but there was no difference in 7-year disease-free survival or overall survival had. CONCLUSION: Repeated alternating administration with PSK followed by 5-FU can improve survival for cancer death.