RESUMO
ST6GalNAc-I, the sialyltransferase responsible for sialyl-Tn (sTn) synthesis, has been previously reported to be positively associated with cancer aggressiveness. Here we describe a novel sTn-dependent mechanism for chemotherapeutic resistance. We show that sTn protects cancer cells against chemotherapeutic-induced cell death by decreasing the interaction of cell surface glycan receptors with galectin-3 and increasing its intracellular accumulation. Moreover, exogenously added galectin-3 potentiated the chemotherapeutics-induced cytotoxicity in sTn non-expressing cells, while sTn overexpressing cells were protected. We also found that the expression of sTn was associated with a reduction in galectin-3-binding sites in human gastric samples tumors. ST6GalNAc-I knockdown restored galectin-3-binding sites on the cell surface and chemotherapeutics sensibility. Our results clearly demonstrate that an interruption of O-glycans extension caused by ST6GalNAc-I enzymatic activity leads to tumor cells resistance to chemotherapeutic drugs, highlighting the need for the development of novel strategies to target galectin-3 and/or ST6GalNAc-I.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Galectina 3/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Animais , Antígenos Glicosídicos Associados a Tumores/genética , Antígenos Glicosídicos Associados a Tumores/metabolismo , Proteínas Sanguíneas , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Galectinas , Glicosilação , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Processamento de Proteína Pós-Traducional , Transporte Proteico , Interferência de RNA , Sialiltransferases/genética , Sialiltransferases/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fatores de Tempo , Transfecção , Carga TumoralRESUMO
Serotyping is a simple typing method that consists of an immunoenzymatic assay (enzyme-linked immunosorbent assay [ELISA]) using synthetic polymorphic peptides derived from Toxoplasma gondii antigens. We developed a new ELISA based on GRA6 C-terminal polymorphic peptides. Serum samples from 41 human infections due to 23 archetypal (type I, II, or III) and 18 nonarchetypal strains were selected in order to validate this approach. For 20 out of the 23 archetypal infections, there was a clear correlation between microsatellite genotype and GRA6 serotyping. All infections due to nonarchetypal strains were misclassified as archetypal strain infections. The GRA6 C-terminal peptides from these strains were analyzed to explain this misclassification. A second group of 455 patients with acute and chronic toxoplasmosis due to unknown genotypes from different European, African, and Latin American countries were included in this study, and the strain type predicted by this method. The results suggest that serotyping is a promising method for typing strains, although limitations exist for African and South American strains as a consequence of higher peptide polymorphism. Other peptides from different markers must be studied in order to discriminate archetypal from nonarchetypal strains.
Assuntos
Antígenos de Protozoários , Proteínas de Protozoários , Toxoplasma/classificação , Toxoplasma/isolamento & purificação , Toxoplasmose/parasitologia , África , Sequência de Aminoácidos , Animais , DNA de Protozoário/genética , Ensaio de Imunoadsorção Enzimática/métodos , Europa (Continente) , Humanos , América Latina , Repetições de Microssatélites , Dados de Sequência Molecular , Sorotipagem/métodos , América do Sul , Estatística como Assunto , Toxoplasma/genética , Toxoplasma/imunologiaRESUMO
PURPOSE: We studied cisplatin plus gemcitabine as induction (neoadjuvant) therapy in patients with stage III non-small cell lung cancer (NSCLC) to assess its objective remission rate, resectability, survival, and toxicity. PATIENTS AND METHODS: Patients with stage III NSCLC received 2 cycles of gemcitabine 1250 mg/m2 on days 1, 8, and 15, plus cisplatin 100 mg/m2 on day 2. Subsequently, patients were assigned to local therapy--surgery or radiotherapy. RESULTS: Twenty-nine eligible patients (male/female: 21/8) with a median age of 59 years (range, 43-71 years) were enrolled between October 1996 and February 1999. A total of 80 cycles were given, with a median of 3 per patient (range, 1-4 cycles). Overall, toxicities were mild; only one patient had febrile neutropenia, and there were no grade 4 non-hematological toxicities. There was one toxic death following afebrile grade 4 neutropenia. Overall clinical response rate (2 complete responses [CRs] + 16 partial responses [PRs]) was 62% (95% CI, 45%-79%); 10 patients had stable disease and none progressed; one patient was not evaluable. Eight of the 18 operated patients had pathological response: 1 CR and 7 downstagings to N(-); 14 patients were resected. Median survival was 17 months (95% CI, 13-21 months), with 1-year and 2-year actuarial survival rates of 61% and 29%, respectively. CONCLUSIONS: Gemcitabine plus cisplatin is a very active and well-tolerated induction regimen in stage III NSCLC. Comparative studies with other standard regimens are warranted.