RESUMO
To evaluate possible improvement in objective response of adding vinorelbine (V) to the combination of cisplatin/gemcitabine (CG) in induction chemotherapy for stage III NSCLC, patients (n=154) aged < or =75 years, Karnofsky index > or =70%, were stratified by stage (IIIA versus IIIB) and randomly assigned to receive: C (50mg/m(2) i.v.) plus G (1250mg/m(2) i.v.) or CG plus V (25mg/m(2) i.v.). All drugs were administered on days 1 and 8 of an every 3-week cycle. At conclusion, local treatment (LT) with surgery and/or radiotherapy was scheduled. The results indicated that, following a median of 3 cycles, the overall efficacy was 65% in the CG and 61% in the CGV group. Most patients in both groups received radiotherapy as part of their LT. Pathological complete response was confirmed by surgery in 18% in the CG and 25% in the CGV group. Median progression-free survival was 368 days in the CG and 322 days in the CGV group. There were no statistically significant differences in toxicities between groups. We conclude that the CG and CGV combinations had similar efficacy and moderate toxicity, without accruing to the triplet combination.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
PURPOSE: Based on the promising results of a Phase I study with a combination of gemcitabine and DTIC performed in advanced soft tissue sarcoma (ASTS) patients, and due to the limited efficacy of second or third line therapies in those patients, we designed a Phase II study to determine the activity of this new regimen. METHODS: Patients with ASTS, measurable disease, pretreated with chemotherapy, received gemcitabine 1,800 mg/m2 infused over 180 min followed by DTIC 500 mg/m2 (one cycle), every 2 weeks. The pharmacokinetics (PK) of gemcitabine and 2',2'-difluorodeoxyuridine (dFdU), and the accumulation of gemcitabine triphosphate (dFdCTP) by peripheral blood mononuclear cells were studied. The influence of the sequence of administration on those parameters was examined to exclude potential drug interactions. RESULTS: Twenty-six patients received a total of 158 cycles (mean four cycles, range 1-18). Grade 3-4 anemia (23% of patients), granulocytopenia (46%) or thrombocytopenia (12%), and grade 3 increase in AST (18%), ALT (21%), or gamma-glutamyl-transferase (9%) were noted. Response rate in 23 patients was 4% (95% CI: 0-24%), and in 8 of 11 patients stable disease lasted > 6 months. Progression-free rate (PFR) at 3 and 6 months was, respectively, 48 and 28%, and median overall survival 37 weeks. Pooled data from the Phase I and Phase II studies showed clinical benefit in patients with leiomyosarcomas (LMS) (57%) and malignant fibrous histiocytomas (MFH) (33%). The sequence of administration did not influence PK of gemcitabine or dFdU. There was a trend (P = 0.11) toward a lower accumulation of dFdCTP when DTIC preceded gemcitabine. CONCLUSIONS: Although the remission rate was low, PFR figures indicate that this regimen has activity in patients with ASTS. It should be compared with DTIC, or other gemcitabine-containing combinations, in patients with LMS or MFH, to determine whether this combination offers advantages in PFR or in overall activity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Adulto , Idoso , Alanina Transaminase/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Aspartato Aminotransferases/sangue , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Dacarbazina/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Ifosfamida/farmacocinética , Infusões Intravenosas , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Sarcoma/metabolismo , Sarcoma/patologia , Temozolomida , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: To explore the prognostic value of mutations in c-KIT and PDGFR-alpha genes with respect to relapse-free survival (RFS) in patients with gastrointestinal stromal tumors (GIST). We have investigated the prognostic relevance of the type and position of the mutations, in addition to other clinicopathologic factors, in a large series of patients with GIST. METHODS: For this study, 162 patients were selected according to the following criteria: completely resected tumors with negative margins attended between 1994 and 2001; no metastasis at diagnosis; tumor larger than 2 cm, c-KIT-positive immunostaining; and no other primary tumors. RESULTS: The median follow-up was 42 months for patients free of recurrence. Mutations were detected in 96 tumors (60%): 82 cases involving c-KIT and 14 cases involving PDFGR-alpha. Univariate analysis demonstrated the following as poor prognostic factors for RFS: tumors larger than 10 cm (P < .0001); mitotic count higher than 10 mitoses per 50 high-power fields (P < .0001); high risk index (P < .0001); intestinal GIST location (P = .0041); high cellularity (P < .0001); tumor necrosis (P < .0001); deletions affecting exon 11 (P = .0007); and deletions affecting codons 557 to 558 (P < .0001). After the multivariate analysis, only the high risk index (relative risk [RR], 12.36), high cellularity (RR, 3.97), and deletions affecting codons 557 to 558 of c-KIT (RR, 2.57) corresponded to independent prognostic factors for RFS in GIST patients. CONCLUSION: Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.
Assuntos
Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Códon , Feminino , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: Gastrointestinal stromal tumors (GIST) are a distinctive group of mesenchymal neoplasms of the gastrointestinal tract. The oncogene KIT has a central role in the pathogenesis of GIST, with c-kit receptor tyrosine kinase (KIT) protein expression being the gold standard in its diagnosis. The identification of GIST patients has become crucial, because the tyrosine kinase inhibitor Imatinib is effective in the treatment of this malignancy. However, a small set of GISTs remain unrecognized, because KIT protein expression is not always evident. The aim of this study was the identification of new markers for the differential diagnosis of GIST. EXPERIMENTAL DESIGN: By analyzing publicly available data from transcriptional profiling of sarcomas, we found that protein kinase C theta (PKC-theta), a novel PKC isotype involved in T-cell activation, is highly and specifically expressed in GIST. PKC-theta expression in GIST was confirmed by reverse transcription-PCR and Western blot. PKC-theta was analyzed by immunohistochemistry in a panel of 26 GIST, 12 non-GIST soft-tissue sarcomas, and 35 tumors from other histologies. RESULTS: We found that all of the GISTs expressed PKC-theta, whereas this protein was undetectable in other mesenchymal or epithelial tumors, including non-GIST KIT-positive tumors. PKC-theta immunoreactivity was also observed in interstitial cells of Cajal. CONCLUSIONS: Our results show that PKC-theta is easily detected by immunohistochemistry in GIST specimens and that it could be a sensitive and specific marker for the diagnosis of this malignancy.
Assuntos
Neoplasias Gastrointestinais/enzimologia , Isoenzimas/biossíntese , Mesoderma/enzimologia , Proteína Quinase C/biossíntese , Células Estromais/enzimologia , Benzamidas , Western Blotting , Regulação da Expressão Gênica , Humanos , Mesilato de Imatinib , Imuno-Histoquímica , Neoplasias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Piperazinas/farmacologia , Isoformas de Proteínas , Proteína Quinase C-theta , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/biossíntese , Pirimidinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma/metabolismo , Linfócitos T/metabolismo , Transcrição GênicaRESUMO
Because no consensus exists regarding recommendable dose levels for irinotecan, an intrapatient dose escalation phase I-II study was initiated in previously treated patients with colorectal cancer. Survival was a secondary endpoint. Thirty-five consecutive patients with progressive disease after 5-fluorouracil-based chemotherapy were enrolled to receive irinotecan starting from 250 mg/m2/3 weeks and rising to currently used therapeutic doses. In total, 162 cycles were administered. The median tolerable dose was 250 mg/m2. Twelve patients (34%) were unable to tolerate doses greater than 250 mg/m2, 10 patients (28%) presented toxicity at 250 mg/m2 and 2 patients tolerated only 200 mg/m2. Three patients (9%) had partial response. The major adverse reactions were grade III-IV diarrhea, grade II-III nausea/vomiting, grade II-III neutropenia, and grade II-III anaemia in 28%, 48%, 11%, and 17% of the patients, respectively. Median survival time and time to progression were 8 and 3 months, respectively. The current irinotecan dose of 350 mg/m2/3 weeks appears unacceptably toxic and, hence, a lower dose needs to be considered. The response rates obtained are similar to the results observed in phase III studies, and its activity appears not to be adversely affected with this treatment scheme.
Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Camptotecina/uso terapêutico , Quimioterapia Adjuvante , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Cuidados Paliativos , Análise de Sobrevida , Inibidores da Topoisomerase I , Falha de TratamentoRESUMO
PURPOSE: To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm. PATIENTS AND METHODS: Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. RESULTS: From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. CONCLUSION: The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dacarbazina/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Terapia de Salvação , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Espanha , Resultado do Tratamento , Adulto Jovem , GencitabinaAssuntos
Antineoplásicos Alquilantes/efeitos adversos , Encefalopatias/induzido quimicamente , Encefalopatias/tratamento farmacológico , Ifosfamida/efeitos adversos , Neoplasias/tratamento farmacológico , Tiamina/administração & dosagem , Adulto , Humanos , Infusões Intravenosas , Resultado do TratamentoRESUMO
Studies with the gemcitabine/vinorelbine (GV) or the gemcitabine/docetaxel (GD) combinations have shown similar efficacy and less toxicity compared to platinum-based chemotherapies, in patients with advanced non-small-cell lung cancer (NSCLC). The present trial was designed to test the efficacy and safety of both, GV and GD, combinations. Chemotherapy-naïve patients (n=39)
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pneumopatias/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Diarreia/induzido quimicamente , Docetaxel , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estudos Prospectivos , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
The objective of this study was to assess whether adding cisplatin to gemcitabine/vinorelbine combination improves the clinical outcome in patients with non-small-cell lung cancer (NSCLC). Chemotherapy-naïve patients with advanced NSCLC; age < or = 75 years: Karnofsky performance status > or = 60%, and with adequate hematological, renal and hepatic function, were randomized into 2 treatment groups to receive Gemcitabine 1250 mg/m2 + vinorelbine 30 mg/m2 (GV group), or cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 (CGV group). All drugs were administered on days 1 and 8 every three weeks: From September 1999 to March 2003, 114 patients were enrolled. No statistically significant difference was observed in GV vs CGV group in objective response (37 versus 47%, respectively; P = 0.5), median time to progression (5 versus 5.8 months; P = 0.6), overall survival (9 versus 10 months; P = 0.9) and 1-year survival (26 versus 28%; P = 0.9). Conversely, toxicities were significantly higher for CGV, including grade 3-4 neutropenia (24 versus 45%); neutropenic fever (4 versus 14%, including one toxic death); grade 3-4 thrombocytopenia (2 versus 14%); and grade 3-4 emesis (2 versus 14%). Our results suggest that the combination of gemcitabine and vinorelbine is less toxic than three-drug combination with cisplatin while showing similar efficacy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
BACKGROUND: The objective of this study was to evaluate the activity and toxicity of temozolomide given as an extended schedule in patients with advanced sarcoma. METHODS: Forty-nine patients with pretreated soft tissue sarcoma (the STS arm) and 18 patients with previously untreated gastrointestinal stromal tumor (the GIST arm) were enrolled onto a 2-arm, multicenter, Phase II study between November 1999 and July 2001. Temozolomide was administered on a 6-week, continuous, oral schedule at a dose of 75 mg/m2 per day in 41 patients and, after an amendment, at a dose of 100 mg/m2 per day in 22 patients. RESULTS: Among 45 eligible patients in the STS arm, there were 7 partial responses, for an overall response rate of 15.5% (95% confidence interval [95% CI], 5-26%). Responses were seen in 5 of 11 patients who had gynecologic leiomyosarcoma. The median response duration was 12.5 months (range, 3.9-58.0 mos). In 4 patients, response lasted > 1 year, and 2 of those patients remained progression free for > 3 years. The median time to progression was 2.2 months (95% CI, 1.8-2.5 mos), and the median overall survival was 8.1 months (95% CI, 5.6-10.6 mos). Progression-free survival rates at 3 months and 6 months were 39.5% and 26%, respectively. In the GIST arm, no responses were noted. Grade 3-4 granulocytopenia, thrombocytopenia, and anemia were observed in 6 patients, 5 patients, and 7 patients, respectively. The most common nonhematologic toxicities were emesis and fatigue. CONCLUSIONS: Temozolomide at the extended schedule was tolerated well and had activity in patients with pretreated soft tissue sarcomas, and especially among patients with gynecologic leiomyosarcoma.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/análogos & derivados , Neoplasias Gastrointestinais/tratamento farmacológico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Administração Oral , Adulto , Idoso , Dacarbazina/uso terapêutico , Esquema de Medicação , Feminino , Neoplasias Gastrointestinais/patologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Taxa de Sobrevida , Temozolomida , Resultado do TratamentoRESUMO
BACKGROUND: In the current study, the authors set out to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) associated with a combination of gemcitabine and dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (ASTS), to obtain preliminary information on the activity of this combination, and to explore possible pharmacodynamic interactions between gemcitabine and DTIC. METHODS: Every 2 weeks, 22 patients with refractory ASTS received fixed-dose rate gemcitabine (10 mg/m2/min) at escalating doses, which ranged from 800 mg/m2 to 2160 mg/m2, plus 500 mg/m2 DTIC. Plasma concentrations of gemcitabine and 2',2'-difluorodeoxyuridine, along with gemcitabine triphosphate (dFdCTP) levels in peripheral blood mononuclear cells (PBMCs), were evaluated during the course of treatment. RESULTS: Grade 3 elevation of transaminase and gamma-glutamyltransferase levels represented the DLT associated with the administration of 2160 mg/m2 gemcitabine plus 500 mg/m2 DTIC. This side effect was reversible, rather than cumulative, and did not exceed Grade 3 in its severity. The doses recommended for use in subsequent Phase II studies are 1800 mg/m2 gemcitabine (administered over the course of 3 hours) and 500 mg/m2 DTIC. Hematologic toxicity was moderate, and nonhematologic side effects that did not exceed Grade 2 in severity included the following: asthenia (75% of patients), fever (59%), nausea (52%), stomatitis (48%), anorexia (44%), emesis (40%), flulike syndrome (37%), and erythematous rash (26%). Alopecia was common. Intracellular dFdCTP levels, which were evaluated in 6 patients, reached a mean maximum value of 209 pmol per 10(6) cells (standard deviation, 59 pmol per 10(6) cells) at the conclusion of gemcitabine administration. DTIC had a limited effect on the elimination of dFdCTP from PBMCs. Objective responses were observed in 5 of the 19 patients who were evaluable for treatment efficacy. CONCLUSIONS: The combination of gemcitabine and DTIC possesses an acceptable toxicity profile and may warrant further investigation in patients with ASTS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Floxuridina/análogos & derivados , Dose Máxima Tolerável , Sarcoma/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/sangue , Relação Dose-Resposta a Droga , Feminino , Floxuridina/sangue , Humanos , Infusões Intravenosas , Leucócitos Mononucleares/química , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , GencitabinaRESUMO
Cohesins are chromosomal proteins that form complexes involved in the maintenance of sister chromatid cohesion during division of somatic and germ cells. Three meiosis-specific cohesin subunits have been reported in mammals, REC8, STAG3 and SMC1 beta; their expression in mouse spermatocytes has also been described. Here we studied the localization of different meiotic and mitotic cohesin components during prophase I in human and murine female germ cells. In normal and atretic human fetal oocytes, from leptotene to diplotene stages, REC8 and STAG3 colocalize in fibers. In murine oocytes, SMC1beta, SMC3 and STAG3 are localized along fibers that correspond first to the chromosome axis and then to the synaptonemal complex in pachytene. Mitotic cohesin subunit RAD21 is also found in fibers that decorate the SC during prophase I in mouse oocytes, suggesting a role for this cohesin in mammalian sister chromatid cohesion in female meiosis. We observed that, unlike human oocytes, murine synaptonemal complex protein SYCP3 localizes to nucleoli throughout prophase I stages, and centromeres cluster in discrete locations from leptotene to dictyate. At difference from meiosis in male mice, the cohesin axis is progressively lost during the first week after birth in females with a parallel destruction of the axial elements at dictyate arrest, demonstrating sexual dimorphism in sister chromatid cohesion in meiosis.
Assuntos
Proteínas Nucleares/análise , Oócitos/química , Animais , Anticorpos/imunologia , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Centrômero/metabolismo , Proteoglicanas de Sulfatos de Condroitina/imunologia , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Cromátides/metabolismo , Proteínas Cromossômicas não Histona/imunologia , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA , Feminino , Imunofluorescência , Proteínas Fúngicas , Humanos , Meiose , Camundongos , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Prófase , CoesinasRESUMO
BACKGROUND: Combinations of high-dose ifosfamide (IF; 10-12 g/m2) plus doxorubicin (DX; 50-90 mg/m2) have been administered to patients with advanced soft tissue sarcoma (ASTS) in an attempt to improve therapeutic efficacy. Although these combination regimens appear to yield higher response rates than do standard-dose regimens, they also are associated with significant hematologic toxicity, despite the administration of hematopoietic growth factor support. As a potentially less toxic alternative, the authors designed a sequential, dose-dense schedule of DX and IF and explored its feasibility and toxicity, as well as patient compliance with the schedule, in a Phase II trial. METHODS: Chemotherapy-naive patients with unresectable locally advanced or metastatic ASTS were to receive DX at 30 mg/m2 per day for 3 consecutive days once every 2 weeks for 3 cycles followed by IF at 12.5 g/m2 delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles. Granulocyte-colony-stimulating factor was administered subcutaneously for 7 days beginning 24 hours after the completion of each DX or IF cycle. Additional IF cycles were allowed if an objective response was achieved. RESULTS: Sixty patients were enrolled in the trial. Three were ineligible, 9 had locally advanced disease, and 48 had metastatic disease. At the completion of therapy, the mean dose intensities for DX and IF were 40 mg/m2 per week and 3.87 g/m2 per week, respectively. Sixty-six percent of patients completed the regimen projected by the protocol. Grade 3 or 4 granulocytopenia, febrile neutropenia, and stomatitis occurred in 46%, 24%, and 27% of patients, respectively. Twenty of 53 assessable patients (38%; 95% confidence interval [CI], 25-51%) achieved objective responses, with a median time to progression of 24 weeks (95% CI, 18-30 weeks). CONCLUSIONS: Sequential administration of dose-dense DX and high-dose IF is feasible and exhibits an acceptable hematologic toxicity profile and a level of activity that is within the range described for schedules that combine high-dose IF with an anthracycline.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Ifosfamida/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sarcoma/mortalidade , Sarcoma/secundário , Neoplasias de Tecidos Moles/mortalidade , Neoplasias de Tecidos Moles/patologia , Resultado do TratamentoRESUMO
Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34-71) and a Karnofsky performance status of 60% (60-80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100 mg/m(2) i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1-32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8-24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.
Assuntos
Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Platina/uso terapêutico , Taxoides/uso terapêutico , Adulto , Idoso , Camptotecina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/sangue , Intervalos de Confiança , Esquema de Medicação , Feminino , Doenças Hematológicas/sangue , Doenças Hematológicas/induzido quimicamente , Humanos , Irinotecano , Avaliação de Estado de Karnofsky/estatística & dados numéricos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
STAG/SA proteins are specific cohesin complex subunits that maintain sister chromatid cohesion in mitosis and meiosis. Two members of this family, STAG1/SA1 and STAG2/SA2,double dagger are classified as mitotic cohesins, as they are found in human somatic cells and in Xenopus laevis as components of the cohesin(SA1) and cohesin(SA2) complexes, in which the shared subunits are Rad21/SCC1, SMC1 and SMC3 proteins. A recently reported third family member, STAG3, is germinal cell-specific and is a subunit of the meiotic cohesin complex. To date, the meiosis-specific cohesin complex has been considered to be responsible for sister chromatid cohesion during meiosis. We studied replacement of the mitotic by the meiotic cohesin complex during mouse germinal cell maturation, and we show that mammalian STAG2 and Rad21 are also involved in several meiosis stages. Immunofluorescence results suggest that a cohesin complex containing Rad21 and STAG2 cooperates with a STAG3-specific complex to maintain sister chromatid cohesion during the diplotene stage of meiosis.
Assuntos
Meiose/fisiologia , Proteínas Nucleares/fisiologia , Fosfoproteínas/fisiologia , Animais , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Imunofluorescência , Camundongos , Mitose/fisiologia , Dados de Sequência Molecular , Proteínas Nucleares/genética , Fosfoproteínas/genética , Prófase/fisiologia , Proteínas de Schizosaccharomyces pombe/fisiologiaRESUMO
A pesar de los resultados atentadores en el control local de los SPB, el falto distal oscila entre un 27% y un 39%, y sólo un pequeño número de los pacientes que fallan puede ser curado con citostáticos, en diversas combinaciones. En esta revision se comentan estudios efectuados con citostáticos después del tratamiento local con cirugía asociada o no a radioterapia