RESUMO
Selective delivery of therapeutic agents into solid tumors has been a major challenge impeding the achievement of long-term disease remission and cure. The need to develop alternative drug delivery routes to achieve higher drug concentration in tumor tissue, reduce unwanted off-target side effects and thus achieve greater therapeutic efficacy, has resulted in an explosive body of research. Bifidobacterium spp. are anaerobic, nonpathogenic, Gram-positive bacteria, commensal to the human gut that are a possible anticancer drug-delivery vehicle. In this review, we describe Bifidobacterium's microbiology, current clinical applications, overview of the preclinical work investigating Bifidobacterium's potential to deliver anticancer therapy, and review the different strategies used up to date. Finally, we discuss both current challenges and future prospects.
Assuntos
Bifidobacterium/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Imunoterapia/métodos , Oncologia/métodos , Neoplasias/terapia , Medicina de Precisão/métodos , Animais , Antineoplásicos/administração & dosagem , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Genes Reporter/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Oncologia/tendências , Neoplasias/genética , Neoplasias/imunologia , Plasmídeos/genética , Medicina de Precisão/tendências , Probióticos/administração & dosagem , Resultado do TratamentoRESUMO
The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency. We initiated development of pbi-shRNA EWS/FLI1 lipoplex (LPX) for the treatment of type 1 Ewing's sarcoma. Clinical-grade plasmid was manufactured and both sequence and activity verified. Target protein and RNA knockdown of 85-92% was demonstrated in vitro in type 1 human Ewing's sarcoma tumor cell lines with the optimal bi-shRNA EWS/FLI1 plasmid. This functional plasmid was placed in a clinically tested, liposomal (LP) delivery vehicle followed by in vivo verification of activity. Type 1 Ewing's sarcoma xenograft modeling confirmed dose related safety and tumor response to pbi-shRNA EWS/FLI1 LPX. Toxicology studies in mini-pigs with doses comparable to the demonstrated in vivo efficacy dose resulted in transient fever, occasional limited hypertension at low- and high-dose assessment and transient liver enzyme elevation at high dose. These results provide the justification to initiate clinical testing.
Assuntos
Lipossomos , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , RNA Interferente Pequeno/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Técnicas de Silenciamento de Genes , Ordem dos Genes , Terapia Genética , Humanos , Mediadores da Inflamação , Masculino , Proteínas de Fusão Oncogênica/administração & dosagem , Proteínas de Fusão Oncogênica/química , Plasmídeos/administração & dosagem , Plasmídeos/genética , Proteína Proto-Oncogênica c-fli-1/administração & dosagem , Proteína Proto-Oncogênica c-fli-1/química , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/química , Proteína EWS de Ligação a RNA/administração & dosagem , Proteína EWS de Ligação a RNA/química , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/patologia , Sarcoma de Ewing/terapia , Reparo Gênico Alvo-Dirigido , Transfecção , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although antitumor activity and a low toxicity profile have been demonstrated for several oncolytic viruses, the development of viral therapy in cancer treatment has been limited by a lack of definitive phase III trials. The use of replicating viruses to potentiate the efficacy of standard cancer therapies also awaits conclusive clinical testing. Based on preliminary results with new generations of oncolytic viruses, ongoing research in this area appears encouraging. This article explores the principles of viral therapy for cancer and the past several decades of investigations with viruses such as Egypt 101, mumps, Newcastle disease, influenza, vaccinia, herpes simplex, and adenovirus serotype 5.
Assuntos
Terapia Biológica/métodos , Neoplasias/terapia , Vírus , Terapia Combinada , Humanos , Neoplasias/virologia , Vírus da Doença de Newcastle , Resultado do Tratamento , Replicação ViralRESUMO
In Part I, the review summarised the safety of adenoviral vectors and provided insight into approaches being undertaken to improve the specificity, durability and potency of adenoviral delivery vehicles. In Part II, brief discussions are held regarding results of preclinical and clinical trials with a variety of different genes, which have demonstrated antitumour activity in squamous cell carcinoma of the head and neck region (HNSCC). Studies have been performed with a variety of immune modulatory genes. Preliminary results demonstrate activity with several cytokine genes, tumour antigen genes and co-stimulatory molecule genes. Despite only preliminary results, thus far, a theoretical attractive feature for the use of gene therapy for the enhancement of immune modulation is that local injection of the gene product appears to be well tolerated. It is also successful in inducing systemic immune response, potentially providing effect to metastatic sites distal from the injected site. Animal studies have confirmed efficacy in the use of specific targeting of molecules regulating cancer growth (EGF receptor [EGFR], super oxide dismutase [SOD], cyclin D1, E1A and Bcl-2). These approaches are discussed. However, the most significant clinical advances for the use of gene therapy in advanced HNSCC involves two agents: Adp53 and ONYX-015. Preliminary Phase I and II results suggest evidence of efficacy and justify accrual Phase III trials, which are currently ongoing.