RESUMO
BACKGROUND: This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients. MATERIALS AND METHODS: Patients were randomly assigned to D 30 mg m(-2) as intravenous infusion (i.v.) and EPI 30 mg m(-2) i.v. every week (D/EPI arm), or D 70 mg m(-2) i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity. RESULTS: A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2-12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7-9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1-30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4-24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated. CONCLUSION: The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Epirubicina/administração & dosagem , Prednisona/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/patologia , Carcinoma/cirurgia , Progressão da Doença , Docetaxel , Esquema de Medicação , Epirubicina/efeitos adversos , Estudos de Viabilidade , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Orquiectomia , Prednisona/efeitos adversos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Taxoides , Falha de TratamentoRESUMO
UNLABELLED: There is evidence that high plasma levels of factor (F) VIII, FIX, FXI and fibrinogen are independent risk factors for venous thromboembolism. AIM: To determine the plasma concentrations of several coagulation factors and C4b-binding protein (C4BP) in a group of patients with non-metastatic colorectal cancer in order to investigate some aspects of cancer-acquired thrombophilia. METHODS: Plasma fibrinogen, FII, FV, FVII, FVIII, FIX, FX, FXI and FXII activity levels and C4BP concentrations were determined in 73 patients with non-metastatic colorectal cancer (48 colon and 25 rectum) and in 67 matched control subjects. No one in either group had had previous thrombotic events. RESULTS: Mean plasma concentrations of fibrinogen (functional and antigen), FVIII, FIX, FV and C4BP were significantly higher in colorectal cancer patients than in control subjects, while FVII and FXII levels were significantly decreased. Several correlations were found between the increased coagulation factors and C4BP concentrations, while FVII was highly correlated with FXII. CONCLUSIONS: In colorectal cancer patients high plasma fibrinogen, FVIII and FIX levels might represent further risk factors for venous thrombotic complications in the immediate post-surgery period, while decreased FVII and FXII concentrations may be an index of intravascular coagulation activation, still in a subclinical phase.
Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Neoplasias Colorretais/sangue , Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/sangue , Reação de Fase Aguda/etiologia , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/complicações , Proteína de Ligação ao Complemento C4b , Feminino , Fibrinogênio/metabolismo , Antígenos de Histocompatibilidade/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Trombofilia/sangue , Trombofilia/etiologiaRESUMO
The aim of this pilot phase II trial was to investigate the toxicity and anti-tumour activity of a novel metronomic regimen of weekly cisplatin (CDDP) and oral etoposide (VP16) in high-risk patients with advanced NSCLC. The study enrolled 31 high-risk patients (27 men and 4 women aged 16-82 years; mean, 64.3) with NSCLC (18 stage IIIB and 13 stage IV) and an ECOG performance status of < or = 3, all of whom received weekly CDDP 30 mg/m2 iv on days 1, 8, 14 and 28 of each cycle and oral daily etoposide 50 mg/m2 on 21 of the 28 days. The most frequent adverse events were grade III leukopenia and anemia; nevertheless, three patients died of pulmonary embolism after 2, 3 and 6 weeks of treatment. The objective response (OR) rate was 45.2% (2 complete and 12 partial), and the disease control rate was 58.1% (14 ORs and 4 disease stabilisations). The mean time to progression and survival were respectively nine months (95% CI, 6.3-15.8 months) and thirteen months (95% CI, 9.1-20.5 months). Pharmacological analysis showed that this metronomic regimen allows a much greater median monthly area under the curve of CDDP and VP16 than conventional treatment schedules. Our findings also suggest that this treatment schedule may affect tumour growth and neoangiogenesis by changing peripheral blood vascular-endothelial growth factor levels. These preliminary results indicate that our metronomic regimen is well tolerated and active, even in patients with a very poor prognosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
To investigate the cis-acting DNA elements that are involved in the regulation of class I major histocompatibility complex genes by interferon, several promoter fragments of the H-2Kk gene were linked to the reporter chloramphenicol acetyl transferase (CAT) gene, and the CAT expression was analyzed in stable transfected cell lines. The functional activities of progressive deletions of the 5'-flanking region of the H-2Kk gene linked to the CAT gene have allowed us to define a discrete cis-acting DNA region necessary for interferon-mediated stimulation. Moreover, the H-2Kk gene transcribed by the nonregulated SV40 early promoter was also found to be under interferon regulation. Thus interferon enhancement of the H-2Kk gene expression appears to be mediated by two cis-acting elements, one located in the 5'-flanking region and the other by sequences downstream from the transcription initiation site.
Assuntos
Genes MHC Classe I , Genes Reguladores , Genes , Antígenos H-2/genética , Interferon Tipo I/fisiologia , Transcrição Gênica , Animais , Clonagem Molecular , Camundongos , Regiões Promotoras Genéticas , TransfecçãoRESUMO
Metronomic chemotherapy is an anticancer strategy which uses conventional cytotoxic drugs administered at very low dose in close intervals. We have designed a phase II trial to investigate the safety and antitumor activity of the newest metronomic chemo-hormonal-therapy with daily cyclophosphamide and twice daily megestrol acetate (mCM regimen) in patients with metastatic pretreated breast cancer.Twenty-nine pretreated post-menopausal patients with multiple metastatic sites were enrolled. four patients had a triple negative status, nineteen a positive hormonal ER and PgR status, and three ERB-B2 over-expression. Patients received treatment with cyclophosphamide (50 mg/daily day 1-21/q28) and fractionated megestrol acetate (80 mg twice a day). The overall objective response rate was 31.0%, disease control rate 41.3%, mean time to tumor progression 7.4 months (CI 95%, 3.8-10.88, range 1-48 months) and mean overall survival 13.4 months (CI 95%, 7.24-17.18, range 1-53 months). The mCM regimen was active and well tolerated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Acetato de Megestrol/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do TratamentoRESUMO
AIMS: Most patients with stage T3-T4 prostate cancer experience disease relapse despite radiation and/or hormonal therapy, and their management remains controversial. We investigated the feasibility of, and the pathological response induced by neoadjuvant chemo-hormonal treatment in men with clinical stage T3/T4. METHODS: Fifteen patients underwent neoadjuvant therapy consisting of weekly intravenous infusions of epirubicin 30mg/m(2) and total androgen blockade (TAB) for three months before undergoing radical prostatectomy, after which all received locoregional conformal radiotherapy (66Gy) and then continued with TAB and three additional months of epirubicin. RESULTS: After neoadjuvant therapy, PSA levels decreased in all 15 patients and became undetectable in two. None of the patients achieved a complete pathological response, but a 35-75% reduction in tumour size was observed in all cases, and all the patients were able to undergo successful prostatectomy. Pathological assessments of the surgical specimens revealed negative margins in 13 patients. After a median follow-up of 34 months (range 11-62), 14 patients (93%) are still clinically and biochemically disease free. No grade 3 or 4 complications occurred. CONCLUSION: This study suggests that neoadjuvant treatment with epirubicin and TAB is feasible and well tolerated in patients with clinical stage T3-T4 prostate cancer.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Epirubicina/administração & dosagem , Terapia Neoadjuvante , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Idoso , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pós-Operatórios/métodos , Cuidados Pré-Operatórios/métodos , Antígeno Prostático Específico/sangue , Prostatectomia/métodos , Neoplasias da Próstata/mortalidade , Radioterapia Adjuvante , Medição de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
GOLF is a triple translational combination chemotherapy regimen with gemcitabine, oxaliplatin, and 5-fluorouracil (5-FU) (plus levofolinic acid), cytotoxic drugs currently used in the treatment of pancreatic carcinoma. Considering its promising anti-tumor effects in patients with gastroenteric malignancies, we carried out the present study to investigate its toxicity and anti-tumor activity in patients with advanced pancreatic carcinoma. Twenty-seven patients were enrolled in the study, 15 males and 12 females with an average age of 61 years and a performance status (ECOG) = 3. Eight of them had already received first-line chemotherapy, 16 had liver involvement and 11 had inoperable locally (nodes, soft tissue infiltration, peritoneum etc) advanced disease. All patients received biweekly gemcitabine (1000 mg/m(2 )on day 1), oxaliplatin (85 mg/m(2 )on day 2); levofolinic acid (100 mg/m 2) and 5-FU (400 mg/m(2 )as bolus, and 800 mg/m(2 )in 24-h infusion) on days 1 and 2. We report one fatal event occurring just after the first cycle due to lung embolism; grade II-III-diarrhea and mucosytis (44.4%); alopecia (37%); thrombocytopenia (18.5%); grade I-II asthenia, fatigue, non-neutropenic-fever (37%) and oxaliplatin-related neurotoxicity (18.5%). We also registered fast pain control in most patients, an objective response and disease control rate of 33.3% and 63% (1 complete and 8 partial responses and 8 disease stabilizations) respectively, with clinical benefit in 60% of patients and median time to progression and overall survival of 5.5 and 8 months, respectively. In conclusion, the GOLF regimen appears to be a feasible treatment for patients with advanced pancreatic carcinoma that deserves to be evaluated in phase III trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , GencitabinaRESUMO
There is evidence that high plasma levels of factor (F) VIII, FIX, FXI and fibrinogen are independent risk factors for venous thromboembolism. AIM: To determine the plasma concentrations of several coagulation factors and C4b-binding protein (C4BP) in a group of patients with non-metastatic colorectal cancer in order to investigate some aspects of cancer-acquired thrombophilia. METHODS: Plasma fibrinogen, FII, FV, FVII, FVIII, FIX, FX, FXI and FXII activity levels and C4BP concentrations were determined in 73 patients with non-metastatic colorectal cancer (48 colon and 25 rectum) and in 67 matched control subjects. No one in either group had had previous thrombotic events. RESULTS: Mean plasma concentrations of fibrinogen (functional and antigen), FVIII, FIX, FV and C4BP were significantly higher in colorectal cancer patients than in control subjects, while FVII and FXII levels were significantly decreased. Several correlations were found between the increased coagulation factors and C4BP concentrations, while FVII was highly correlated with FXII. CONCLUSIONS: In colorectal cancer patients high plasma fibrinogen, FVIII and FIX levels might represent further risk factors for venous thrombotic complications in the immediate post-surgery period, while decreased FVII and FXII concentrations may be an index of intravascular coagulation activation, still in a subclinical phase.
RESUMO
We report the results of a phase II trial in patients with metastatic endocrine tumours from different sites, which aimed to evaluate the anti-tumour activity and toxicity of a cisplatinum and etoposide regimen administered in combination with the somatostatin agonist lanreotide given in slow release formulation. Between January 1999 and November 2003, 27 patients with histological diagnoses of endocrine tumours with different degrees of differentiation, excluding well differentiated carcinoid neoplasms, received intravenous (i.v.) administration of cisplatinum (30 mg m(-2)) and etoposide (100 mg m(-2)) on days 1-3 and intramuscular administration of 60 mg lanreotide on day 1, in a 21-day cycle. All of the patients were evaluable for toxicity and response. The treatment was very well tolerated as no grade 4 toxicity was observed. Four patients achieved a complete response, six a partial response, 12 experienced disease stabilisation and five disease progression. The average time to progression and to survival were 9 and 24 months respectively. These results suggest that this chemo-hormone therapy regimen is well tolerated and active in patients with non-well differentiated endocrine tumours.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Glândulas Endócrinas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Cisplatino/administração & dosagem , Estudos de Coortes , Preparações de Ação Retardada , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/administração & dosagem , Somatostatina/administração & dosagem , Somatostatina/análogos & derivadosRESUMO
The finger motif is a tandemly repeated DNA-binding domain recently identified in the primary structure of several eukaryotic transcriptional regulatory proteins. It was first described for Xenopus TFIIIA, a factor required for transcription of 5S ribosomal genes and subsequently identified in regulatory proteins from other eukaryotic organisms including yeast, Drosophila and mammals. In this paper we report the isolation and characterization of two human cDNA clones both encoding for multifingered protein products. Transcriptional studies indicate that the two finger genes are expressed in a variety of human tissues. Moreover, upon in vitro induced terminal differentiation of human HL-60 and THP-1 myeloid cell lines the expression of both genes is drastically reduced. These data provide support for the existence of a human multigene family coding for regulatory finger proteins which are likely involved in the processes of cell differentiation and/or proliferation.
Assuntos
Proteínas de Ligação a DNA/genética , DNA/isolamento & purificação , Genes , RNA Mensageiro/genética , Transcrição Gênica , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular , Clonagem Molecular , DNA/genética , Humanos , Dados de Sequência MolecularRESUMO
We used the chloramphenicol acetyl transferase (CAT) transient expression system to study the transactivating ability of a simian virus 40 (SV40) mutant that was unable to transport and localize large T antigen into the nucleus and which retained the competence to transform established cell lines. The effect of the SV40 wild type and the SV40 mutant for the large T antigen was tested in both mouse and simian cells on a series of plasmids in which the CAT gene was regulated by one of the following promoters: SV40 early and late, herpes simplex virus thymidine kinase, chicken alpha 2(I) collagen, mouse H-2Kk. Our results indicated that both the SV40 wild type and the cytoplasmic mutant for the large T antigen regulated transcription from any promoter tested, suggesting that the trans-activation by SV40 does not require the nuclear localization of the 100,000-molecular-weight large T-antigen protein.
Assuntos
Antígenos Virais de Tumores/metabolismo , Transformação Celular Viral , Genes Virais , Proteínas Oncogênicas Virais/metabolismo , Regiões Promotoras Genéticas , Proteínas Quinases/metabolismo , Vírus 40 dos Símios/genética , Ativação Viral , Animais , Antígenos Transformantes de Poliomavirus , Antígenos Virais de Tumores/genética , Linhagem Celular , Células Cultivadas , Mutação , Proteínas Oncogênicas Virais/genéticaRESUMO
We have identified new repeated interspersed DNA sequences by analysis of homologous RNA transcripts from a human teratocarcinoma cell line (NTERA-2 clone D1). The abundance of transcripts varies upon retinoic acid induced differentiation of NTERA-2/D1 cells, and it is highest when the cells display the embryonal carcinoma phenotype. The expression of these novel repeated sequences appears to be tissue specific as no detectable expression was found in various cell lines of different embryological derivation. Characterization of the RNA transcripts by analysis of recombinant cDNA clones indicated that transcripts of different genomic units are present in undifferentiated embryonal teratocarcinoma cells. Nucleotide sequencing of the cloned cDNAs reveals a complex structure composed by unique and tandemly repeated sub-elements.
Assuntos
DNA/genética , Sequências Repetitivas de Ácido Nucleico , Teratoma/genética , Sequência de Bases , Códon , Regulação da Expressão Gênica , Humanos , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , RNA/análise , RNA/genética , Mapeamento por Restrição , Transcrição Gênica , Tretinoína/farmacologia , Células Tumorais CultivadasRESUMO
On the basis of sequence similarity in the repeated zinc finger domain, we have identified and characterized two human cDNA clones (ZNF7 and ZNF8), both encoding proteins containing potential finger-like nucleic acid binding motifs. Northern blot analysis indicates that both genes are expressed as multiple transcripts and they are ubiquitously present in many human cell lines of different embryological derivation. Moreover, their expression is modulated during in vitro induced terminal differentiation of human myeloid cell line HL-60. By in situ hybridization experiments, we have localized the ZNF7 gene to chromosome 8 (region q24) and the ZNF8 gene to the terminal band of the long arm of chromosome 20 (20q13).
Assuntos
Cromossomos Humanos Par 20 , Cromossomos Humanos Par 8 , Proteínas de Ligação a DNA/genética , Expressão Gênica , Genes , Metaloproteínas/genética , Sequência de Aminoácidos , Sequência de Bases , Northern Blotting , Diferenciação Celular , Linhagem Celular , Mapeamento Cromossômico , Clonagem Molecular , DNA/genética , DNA/isolamento & purificação , Feminino , Humanos , Fatores de Transcrição Kruppel-Like , Dados de Sequência Molecular , Homologia de Sequência do Ácido Nucleico , Transcrição Gênica , ZincoRESUMO
The finger motif is a tandemly repeated DNA-binding domain recently identified in the primary structure of several eukaryotic transcriptional regulatory proteins. It has been proposed that some members of the finger-gene family are implicated in both normal cell proliferation and differentiation. We isolated several human finger genes by means of hybridization with a finger motif-containing DNA probe. One of these finger genes, HF.10, is expressed at low levels in a variety of human tissues and is down-regulated during the in vitro terminal differentiation of human leukemic myeloid cell lines. By in situ hybridization experiments and analysis of interspecific somatic cell hybrids we mapped the HF.10 gene to 3p21-22, a chromosome region frequently involved in karyotypic rearrangements associated with lung and renal cancer.