RESUMO
Cyclophosphamide is an alkylating agent used to treat cats with lymphoma, carcinomas and sarcomas. However, no clear consensus exists regarding the maximum tolerated dose (MTD) of oral cyclophosphamide in cats. Toxicities are rarely reported at published oral dosages of cyclophosphamide (200-300 mg/m2). The primary aim of this prospective study was to determine the MTD of oral cyclophosphamide in tumour-bearing cats via a modified phase I trial. A secondary aim was to define any toxicity. Forty-six client-owned tumour-bearing cats were enrolled. The cyclophosphamide dosage was escalated by approximately 10% (300, 330, 360, 400, 440, 460 and 480 mg/m2) in cohorts of at least six cats. The MTD of oral cyclophosphamide in this study was 460 mg/m2 with an inter-treatment interval of two to three weeks. Haematology is recommended 7 and 14 days after first cyclophosphamide treatment, and immediately before each subsequent dosage of cyclophosphamide or any potentially myelosuppressive chemotherapy agent. The dose-limiting toxicity was neutropenia with nadir at 7-21 days. This higher dosage was considered safe in combination with prednisolone and L-asparaginase. However, the higher dose of oral cyclophosphamide has not been evaluated in combination with other chemotherapy agents and thus should not be administered with these agents.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Doenças do Gato/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Dose Máxima Tolerável , Neoplasias/veterinária , Administração Oral , Animais , Antineoplásicos Alquilantes/toxicidade , Gatos , Ciclofosfamida/toxicidade , Neoplasias/tratamento farmacológico , Estudos ProspectivosRESUMO
To develop effective therapies for advanced high grade serous ovarian cancer (HGSOC), understanding mechanisms of recurrence and metastasis is necessary. In this study, we define the epithelial/mesenchymal status of cell lines that accurately model HGSOC, and evaluate the therapeutic potential of targeting Snai1 (Snail), a master regulator of the epithelial/mesenchymal transition (EMT) in vitro and in vivo. The ratio of Snail to E-cadherin (S/E index) at RNA and protein levels was correlated with mesenchymal morphology in four cell lines. The cell lines with high S/E index (OVCAR8 and COV318) showed more CSC-like, motile, and chemoresistant phenotypes than those with low S/E index (OVSAHO and Kuramochi). We tested the role of Snail in regulation of malignant phenotypes including stemness, cell motility, and chemotherapy resistance: shRNA-mediated knockdown of Snail reversed these malignant phenotypes. Interestingly, the expression of let-7 tumour suppressor miRNA was upregulated in Snail knockdown cells. Furthermore, knockdown of Snail decreased tumour burden in an orthotopic xenograft mouse model. We conclude that Snail is important in controlling HGSOC malignant phenotypes and suggest that the Snail/Let-7 axis may be an attractive target for HGSOC treatment.
Assuntos
Transição Epitelial-Mesenquimal , Proteínas de Neoplasias/genética , Neoplasias Experimentais , Células-Tronco Neoplásicas , Neoplasias Ovarianas , Fatores de Transcrição da Família Snail/genética , Animais , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Fatores de Transcrição da Família Snail/metabolismoRESUMO
In veterinary medical oncology, there is currently no standardized protocol for assessing response to therapy in solid tumours. The lack of such a formalized guideline makes it challenging to critically compare outcome measures across various treatment protocols. The Veterinary Cooperative Oncology Group (VCOG) membership consensus document presented here is based on the recommendations of a subcommittee of American College of Veterinary Internal Medicine (ACVIM) board-certified veterinary oncologists. This consensus paper has used the human response evaluation criteria in solid tumours (RECIST v1.1) as a framework to establish standard procedures for response assessment in canine solid tumours that is meant to be easy to use, repeatable and applicable across a variety of clinical trial structures in veterinary oncology. It is hoped that this new canine RECIST (cRECIST v1.0) will be adopted within the veterinary oncology community and thereby facilitate the comparison of current and future treatment protocols used for companion animals with cancer.
Assuntos
Doenças do Cão/diagnóstico , Doenças do Cão/terapia , Neoplasias/veterinária , Medicina Veterinária/normas , Animais , Consenso , Intervalo Livre de Doença , Cães , Humanos , Oncologia , Neoplasias/diagnóstico , Neoplasias/terapia , Médicos VeterináriosRESUMO
The Arabidopsis bas1-D mutation suppresses the long hypocotyl phenotype caused by mutations in the photoreceptor phytochrome B (phyB). The adult phenotype of bas1-D phyB-4 double mutants mimics that of brassinosteroid biosynthetic and response mutants. bas1-D phyB-4 has reduced levels of brassinosteroids and accumulates 26-hydroxybrassinolide in feeding experiments. The basis for the mutant phenotype is the enhanced expression of a cytochrome P450 (CYP72B1). bas1-D suppresses a phyB-null allele, but not a phyA-null mutation, and partially suppresses a cryptochrome-null mutation. Seedlings with reduced BAS1 expression are hyperresponsive to brassinosteroids in a light-dependent manner and display reduced sensitivity to light under a variety of conditions. Thus, BAS1 represents one of the control points between multiple photoreceptor systems and brassinosteroid signal transduction.
