RESUMO
A biosimilar is a biologic product that is similar to a reference biopharmaceutical product, the manufacturing process of which hinders the ability to identically replicate the structure of the original product, and therefore, it cannot be described as an absolute equivalent of the original medication. The currently available technology does not allow for an accurate copy of complex molecules, but it does allow the replication of similar molecules with the same activity. As biosimilars are about to be introduced in oncology practice, these must be evaluated through evidence-based medicine. This manuscript is a position paper, where the Brazilian Society of Clinical Oncology (SBOC) aims to describe pertinent issues regarding the approval and use of biosimilars in oncology. As a working group on behalf of SBOC, we discuss aspects related to definition, labeling/nomenclature, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, and the potential impact on financial burden in healthcare. We take a stand in favor of the introduction of biosimilars, as they offer a viable, safe, and cost-effective alternative to the biopharmaceutical products currently used in cancer. We hope this document can provide valuable information to support therapeutic decisions that maximize the clinical benefit for the thousands of cancer patients in Brazil and can contribute to expedite the introduction of this new drug class in clinical practice. We expect the conveyed information to serve as a basis for further discussion in Latin America, this being the first position paper issued by a Latin American Oncology Society.
Assuntos
Medicamentos Biossimilares/uso terapêutico , Oncologia , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Medicamentos Biossimilares/economia , Medicamentos Biossimilares/normas , Brasil , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Humanos , Neoplasias/imunologia , Farmacovigilância , Sociedades MédicasRESUMO
A biosimilar is a biologic product that is similar to a reference biopharmaceutical product, the manufacturing process of which hinders the ability to identically replicate the structure of the original product, and therefore, it cannot be described as an absolute equivalent of the original medication. The currently available technology does not allow for an accurate copy of complex molecules, but it does allow the replication of similar molecules with the same activity. As biosimilars are about to be introduced in oncology practice, these must be evaluated through evidence-based medicine. This manuscript is a position paper, where the Brazilian Society of Clinical Oncology (SBOC) aims to describe pertinent issues regarding the approval and use of biosimilars in oncology. As a working group on behalf of SBOC, we discuss aspects related to definition, labeling/nomenclature, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, and the potential impact on financial burden in healthcare. We take a stand in favor of the introduction of biosimilars, as they offer a viable, safe, and cost-effective alternative to the biopharmaceutical products currently used in cancer. We hope this document can provide valuable information to support therapeutic decisions that maximize the clinical benefit for the thousands of cancer patients in Brazil and can contribute to expedite the introduction of this new drug class in clinical practice. We expect the conveyed information to serve as a basis for further discussion in Latin America, this being the first position paper issued by a Latin American Oncology Society.
Assuntos
Humanos , Medicamentos Biossimilares/uso terapêutico , Oncologia , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Medicamentos Biossimilares/economia , Medicamentos Biossimilares/normas , Brasil , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Neoplasias/imunologia , Farmacovigilância , Sociedades MédicasRESUMO
Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.
Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Carcinoma de Células Escamosas/radioterapia , Neoplasias do Colo do Útero/radioterapia , Genes p53/efeitos da radiação , Genes erbB-1/efeitos da radiação , Proteínas de Ligação a DNA/efeitos da radiação , Endonucleases/efeitos da radiação , Imuno-Histoquímica , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Ensaio Tumoral de Célula-Tronco , Western Blotting , Estudos Prospectivos , Linhagem Celular Tumoral , MutaçãoRESUMO
Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Proteínas de Ligação a DNA/efeitos da radiação , Endonucleases/efeitos da radiação , Genes erbB-1/efeitos da radiação , Genes p53/efeitos da radiação , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Reparo do DNA/efeitos da radiação , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta à Radiação , Endonucleases/metabolismo , Receptores ErbB/metabolismo , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Resultado do Tratamento , Ensaio Tumoral de Célula-Tronco , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
We examined the degeneration of post-mitotic ganglion cells in ex-vivo neonatal retinal explants following axon damage. Ultrastructural features of both apoptosis and autophagy were detected. Degenerating cells reacted with antibodies specific for activated caspase-3 or -9, consistent with the presence of caspase activity. Furthermore, peptidic inhibitors of caspase-9, -6 or -3 prevented cell death (100 µM Ac-LEDH-CHO, 50 µM Ac-VEID-CHO and 10 µM Z-DEVD-fmk, respectively). Interestingly, inhibition of autophagy by 7-10 mM 3-methyl-adenine increased the rate of cell death. Immunohistochemistry data, caspase activation and caspase inhibition data suggest that axotomy of neonatal retinal ganglion cells triggers the intrinsic apoptotic pathway, which, in turn, is counteracted by a pro-survival autophagic response, demonstrated by electron microscopy profiles and pharmacological autophagy inhibitor.
Assuntos
Animais , Ratos , Apoptose/fisiologia , Autofagia/fisiologia , Caspase 9/metabolismo , /metabolismo , Células Ganglionares da Retina/enzimologia , Axotomia , Autofagia/efeitos dos fármacos , Imuno-Histoquímica , Microscopia Eletrônica de Transmissão , Células Ganglionares da Retina/ultraestruturaRESUMO
We examined the degeneration of post-mitotic ganglion cells in ex-vivo neonatal retinal explants following axon damage. Ultrastructural features of both apoptosis and autophagy were detected. Degenerating cells reacted with antibodies specific for activated caspase-3 or -9, consistent with the presence of caspase activity. Furthermore, peptidic inhibitors of caspase-9, -6 or -3 prevented cell death (100 µM Ac-LEDH-CHO, 50 µM Ac-VEID-CHO and 10 µM Z-DEVD-fmk, respectively). Interestingly, inhibition of autophagy by 7-10 mM 3-methyl-adenine increased the rate of cell death. Immunohistochemistry data, caspase activation and caspase inhibition data suggest that axotomy of neonatal retinal ganglion cells triggers the intrinsic apoptotic pathway, which, in turn, is counteracted by a pro-survival autophagic response, demonstrated by electron microscopy profiles and pharmacological autophagy inhibitor.