RESUMO
The aim of this prospective open-label study was to evaluate the efficacy and safety of oral vinorelbine in combination with capecitabine in patients with metastatic breast cancer (MBC). 51 patients with MBC received oral vinorelbine and capecitabine. The safety profile was analyzed through NCI-CTCAE v3.0 and response was evaluated using RECIST criteria. The overall response rate was 37.2%: there were four complete responders (8%) and fifteen partial responders (29.4%); practically all the responders were patients previously treated with anthracyclines and taxanes. Sixteen patients (31.3%) experienced stable disease. The clinical benefit rate was 68.5%. The median time to progression was 8 months (range 2-43; 95% CI: 6-10.8). Vinorelbine in combination with capecitabine is an effective and safe schedule for patients with MBC especially after pretreatment with anthracycline/ taxane-based regimens. The clinical benefit suggests that this may be a promising schedule in the MBC initial treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Vimblastina/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mama/patologia , Neoplasias da Mama/secundário , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , VinorelbinaRESUMO
BACKGROUND: Through different pharmacodynamic-kinetic interactions, weekly administration of proved efficacy agents can overcome resistance with lower toxicity and greater benefit. Based on this assumption, we designed a phase I-II trial with weekly non-pegylated liposomal anthracycline and taxane in first-line breast cancer patients. PATIENTS AND METHODS: We enrolled 56 previously untreated metastatic breast cancer patients; they were randomly assigned to receive paclitaxel (Taxol) (50 mg/mq) or docetaxel (Taxotere) (30 mg/mq) combined with non-pegylated liposomal anthracycline (25 mg/mq) on days 1, 8 and 15 every 4 weeks. The primary end points were the clinical benefit and treatment-related toxic effects assessment. Secondary end points were time-to-disease progression (TTP) and overall survival (OS). RESULTS: The overall clinical benefit was 87.04%. World Health Organization G3-4 toxic effects included neutropenia (45%), anemia (44%), complete alopecia (83%), severe onycholysis and neuropathy. The 24% of patients developed left ventricular ejection fraction reduction but none >10% with recover after treatment completion. The median absolute decrease from baseline was 1%. Median TTP was 11 months and median OS was 23 months. CONCLUSIONS: Combined weekly administration of taxane and non-pegylated liposomal anthracycline is well tolerated and clinical benefit data encourage phase III study design.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/uso terapêutico , Taxoides/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Doxorrubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Taxoides/administração & dosagemRESUMO
The Met tyrosine kinase - the HGF receptor - induces cell transformation and metastasis when constitutively activated. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines which act as docking sites for a number of SH2-containing molecules. These include Grb2 and p85 which couple the receptor, respectively, with Ras and PI 3-kinase. We previously showed that a Met mutant designed to obtain preferential coupling with Grb2 (Met2xGrb2) is permissive for motility, increases transformation, but - surprisingly - is impaired in causing invasion and metastasis. In this work we used Met mutants optimized for binding either p85 alone (Met2xPI3K) or p85 and Grb2 (MetPI3K/Grb2) to evaluate the relative importance of Ras and PI 3-kinase as downstream effectors of Met. Met2xPI3K was competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, MetP13K/Grb2 induced motility, transformation, invasion and metastasis as efficiently as wild type Met. Furthermore, the expression of constitutively active PI 3-kinase in cells transformed by the Met2xGrb2 mutant, fully rescued their ability to invade and metastasize. These data point to a central role for PI 3-kinase in Met-mediated invasiveness, and indicate that simultaneous activation of Ras and PI 3-kinase is required to unleash the Met metastatic potential.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Transformação Celular Neoplásica , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Sequência de Aminoácidos , Animais , Células COS , Sequência Consenso , Cães , Ativação Enzimática , Fibroblastos/citologia , Proteína Adaptadora GRB2 , Camundongos , Camundongos Nus , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Ratos , Proteínas Recombinantes/metabolismo , Transdução de SinaisRESUMO
The sequence encoding the endopolygalacturonase (PG) of Fusarium moniliforme was cloned into the E. coli/yeast shuttle vector Yepsec1 for secretion in yeast. The recombinant plasmid (pCC6) was used to transform Saccharomyces cerevisiae strain S150-2B; transformed yeast cells were able to secrete PG activity into the culture medium. The enzyme (wtY-PG) was purified, characterized, and shown to possess biochemical properties similar to those of the PG purified from F. moniliforme. The wtY-PG was able to macerate potato medullary tissue disks and was inhibited by the polygalacturonase-inhibiting protein (PGIP) purified from Phaseolus vulgaris. The sequence encoding PG in pCC6 was subjected to site-directed mutagenesis. Three residues in a region highly conserved in all the sequences known to encode PGs were separately mutated: His 234 was mutated into Lys (H 234-->K), and Ser 237 and Ser 240 into Gly (S 237-->G and S 240-->G). Each of the mutated sequences was used to transform S. cerevisiae and the mutated enzymes were purified and characterized. Replacement of His 234 with Lys abolished the enzymatic activity, confirming the biochemical evidence that a His residue is critical for enzyme activity. Replacement of either Ser 237 or Ser 240 with Gly reduced the enzymatic activity to 48% and 6%, respectively, of the wtY-PG. When applied to potato medullary tissue, F. moniliforme PG and wtY-PG caused comparable maceration, while the variant PGs exhibited a limited (S 234-->G and S 240-->G) or null (H 234-->K) macerating activity. The interaction between the variant enzymes and the P. vulgaris PGIP was investigated using a biosensor based on surface plasmon resonance (BIAlite). The three variant enzymes were still able to interact and bind to PGIP with association constants comparable to that of the wild type enzyme.
Assuntos
Fusarium/enzimologia , Histidina , Poligalacturonase/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Sítios de Ligação , Clonagem Molecular , Sequência Conservada , Primers do DNA , Inibidores Enzimáticos/metabolismo , Fabaceae , Mutagênese Sítio-Dirigida , Proteínas de Plantas/metabolismo , Plantas Medicinais , Poligalacturonase/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiaeRESUMO
The biological effects of hepatocyte growth factor/scatter factor are mediated by autophosphorylation of its receptor, the Met tyrosine kinase, on two carboxyl-terminal tyrosines. These phosphotyrosines (Y1349VHVNATY1356VNV) are multifunctional docking sites for several effectors. Grb2, the adaptor for the Ras guanyl-nucleotide exchanger SOS, binds to Tyr1356 in the YVNV motif. By site-directed mutagenesis we either abrogated or duplicated the Grb2 consensus, without interfering with the other effectors. Loss of the link with Grb2 severely impaired transformation. The same mutation, however, had no effect on the "scattering" response, indicating that the level of signal which can be reached by Grb2-independent routes is permissive for motility. Duplication of the Grb2 binding site enhanced transformation and left motility unchanged. Thus, two Met-mediated biological responses, motility and growth, can be dissociated on the basis of their differential requirement for a direct link with Ras.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Células 3T3 , Sequência de Aminoácidos , Animais , Sequência de Bases , Western Blotting , Proteínas Quinases Dependentes de Cálcio-Calmodulina/efeitos dos fármacos , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Linhagem Celular , Células Cultivadas , Cães , Receptores ErbB/metabolismo , Proteína Adaptadora GRB2 , Fator de Crescimento de Hepatócito/farmacologia , Humanos , Rim , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Fatores de Crescimento Neural/farmacologia , Oligodesoxirribonucleotídeos , Fosfopeptídeos/química , Fosfotirosina , Mutação Puntual , Proteínas/química , Proteínas/isolamento & purificação , Proteínas Proto-Oncogênicas c-met , Ratos , Ratos Endogâmicos F344 , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/isolamento & purificação , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/isolamento & purificação , Mapeamento por Restrição , Transformação Genética , Células Tumorais CultivadasRESUMO
The authors present different kinds of laser used in the treatment of several surgical affections in out patients. A review of the international literature and main uses of this technique are shown.
Assuntos
Assistência Ambulatorial , Terapia a Laser , Humanos , Pacientes AmbulatoriaisRESUMO
Thymic carcinoid is a rare lesion. Two cases are reported and diagnostic as well as therapeutic problems are discussed.