RESUMEN
A prospective dose escalation pilot study was performed in cancer-bearing cats to assess toxicity and surrogate biomarkers of pharmacologic activity of oral metformin hydrochloride. Nine cats with measurable spontaneous cancer were treated with oral metformin for 14 days. Monitoring included complete blood count (CBC), serum biochemistry, lactate, pH, insulin-like growth factor-1, and vascular endothelial growth factor serially until study completion. At the maximum tolerated dose of 10 mg kg-1 q12 h side effects were primarily mild to moderate gastrointestinal upset (anorexia, vomiting, and/or weight loss). All cats developed a reduction in haematocrit. Six of nine cats developed new or progressive hyperlactatemia and one cat developed asymptomatic lactic acidosis. There were no clinical responders and two cats had modest measurable reduction in tumour size. In conclusion, we demonstrate potential pharmacologic activity of metformin at a clinically relevant dose and identify parameters for clinical monitoring and supportive care. Further investigation of metformin in cancer-bearing cats is warranted.
Asunto(s)
Antineoplásicos/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Metformina/uso terapéutico , Neoplasias/veterinaria , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Gatos , Femenino , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Metformina/administración & dosificación , Metformina/efectos adversos , Neoplasias/tratamiento farmacológico , Proyectos Piloto , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Cathepsin K (CatK) is a lysosomal protease with collagenolytic activity, and its secretion by osteoclasts is responsible for degrading organic bone matrix. People with pathologic bone resorption have higher circulating CatK concentrations. HYPOTHESIS: Canine osteosarcoma (OS) cells will possess CatK, and its secretion will be cytokine inducible. Circulating CatK concentrations will be increased in dogs with OS, and will be a surrogate marker of bone resorption. ANIMALS: Fifty-one dogs with appendicular OS and 18 age- and weight-matched healthy control dogs. METHODS: In a prospective study, expressions of CatK mRNA and protein were investigated in OS cells. The inducible secretion and proteolytic activity of CatK from OS cells was assessed in vitro. Serum CatK concentrations were quantified in normal dogs and dogs with OS and its utility as a bone resorption marker was evaluated in dogs with OS treated with palliative radiation and antiresorptive agents. RESULTS: Canine OS cells contain preformed CatK within cytoplasmic vesicles. In OS cells, TGFß1 induced the secretion of CatK, which degraded bone-derived type I collagen in vitro. CatK concentrations were higher in dogs with OS than healthy dogs (11.3 ± 5.2 pmol/L versus 8.1 ± 5.0 pmol/L, P = .03). In a subset of dogs with OS, pretreatment CatK concentrations gradually decreased after palliative radiation and antiresorptive treatment, from 9.3 ± 3.2 pmol/L to 5.0 ± 3.1 pmol/L, P = .03. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine OS is associated with pathologic bone resorption, and CatK inhibitors might aid in the management of canine OS-related malignant osteolysis.
Asunto(s)
Neoplasias Óseas/veterinaria , Catepsina K/biosíntesis , Enfermedades de los Perros/enzimología , Osteosarcoma/veterinaria , Animales , Western Blotting/veterinaria , Conservadores de la Densidad Ósea/farmacología , Neoplasias Óseas/enzimología , Catepsina K/genética , Línea Celular Tumoral , Colágeno Tipo I/metabolismo , Perros , Inmunohistoquímica/veterinaria , Osteosarcoma/enzimología , Estudios Prospectivos , ARN/química , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
BACKGROUND: Canine osteosarcoma (OSA) causes focal malignant osteolysis leading to severe pain. Despite the documented efficacy of radiotherapy or IV aminobisphosphonates for managing cancer bone pain, their potential combined therapeutic value has not been reported in OSA-bearing dogs. HYPOTHESIS: Pamidronate combined with standardized palliative therapy will improve pain control and bone biologic effects in OSA-bearing dogs. ANIMALS: Fifty dogs with appendicular OSA treated with standardized palliative therapy and either pamidronate or sterile saline. METHODS: Randomized, prospective, double-blinded, placebo-controlled study. Treatment responses for dogs receiving standardized palliative therapy with (n = 26) or without (n = 24) adjuvant pamidronate were serially evaluated for changes in subjective pain scores, urine N-telopeptide (NTx) excretion, primary tumor relative bone mineral density (rBMD), and computerized pressure platform gait analysis. RESULTS: Median duration of subjective pain relief for dogs treated with adjuvant pamidronate or placebo was 76 and 75 days, respectively (P= .39). Forty percent (20/50; pamidronate [11/26] and placebo [9/24]) of dogs experienced durable analgesia, defined by pain alleviation > or =112 days. For patients achieving durable pain control, dogs treated with pamidronate achieved greater reductions in NTx excretion and larger increases in rBMD compared with placebo controls. Changes in peak vertical force assessed by computerized pressure platform gait analysis correlated with pain alleviation in OSA-bearing dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Combining pamidronate with standardized palliative therapy is safe, but does not clearly improve pain alleviation. However, in dogs achieving durable pain control, adjuvant pamidronate appears to decrease focal bone resorption in the local tumor microenvironment.
Asunto(s)
Difosfonatos/administración & dosificación , Difosfonatos/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Manejo del Dolor , Radioterapia/veterinaria , Analgesia/veterinaria , Analgésicos/administración & dosificación , Analgésicos/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/radioterapia , Perros , Método Doble Ciego , Extremidades/patología , Femenino , Masculino , Osteosarcoma/complicaciones , Osteosarcoma/veterinaria , PamidronatoRESUMEN
BACKGROUND: Various bone resorption markers in humans are useful for supporting the diagnosis of malignant skeletal pathology, with certain bone resorption markers appearing to be more discriminatory for detecting cancer-induced osteolysis than others. Canine osteosarcoma (OSA) is characterized by focal bone destruction, but a systematic investigation for determining which bone resorption marker best supports the diagnosis of OSA in dogs has not been reported. HYPOTHESIS: Dogs with OSA will have increased concentrations of bone resorption markers compared with healthy dogs and dogs with orthopedic disorders. Differences will exist among various bone resorption markers for their ability to support the diagnosis of malignant osteolysis in dogs with OSA. ANIMALS: Single time point, cross-sectional, cohort study including dogs with OSA (n = 20) or orthopedic disorders (n = 20) and healthy dogs (n = 22). METHODS: Basal concentrations of urine and serum N-telopeptide (NTx), urine and serum C-telopeptide (CTx), and urine deoxypyridinoline (DPD) were compared among all 3 groups. RESULTS: Compared with healthy dogs and dogs with orthopedic disorders, urine NTx, serum NTx, and serum CTx concentrations were significantly increased in dogs with OSA. For urine NTx and serum NTx, the calculated lower and upper 95% confidence limits in dogs with OSA did not overlap with dogs diagnosed with orthopedic disorders or healthy dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Of the markers evaluated in this study, urine NTx and serum NTx appear to be the most discriminatory resorption markers supporting the diagnosis of focal malignant osteolysis in dogs with OSA.
Asunto(s)
Biomarcadores/sangre , Biomarcadores/orina , Resorción Ósea/metabolismo , Enfermedades de los Perros/metabolismo , Osteoartritis/veterinaria , Osteosarcoma/veterinaria , Animales , Perros , Femenino , Masculino , Osteoartritis/metabolismo , Osteosarcoma/metabolismoRESUMEN
BACKGROUND: Feline oral squamous cell carcinoma (OSCC) may cause painful bone destruction. Given the local invasiveness and rapid clinical progression of OSCC, conventional therapies are often palliative. In human cancer patients, zoledronate exerts anticancer effects by inhibiting tumor-induced angiogenesis and malignant osteolysis. HYPOTHESIS: Zoledronate will exert in vitro and in vivo anti-angiogenic and antiresorptive effects in feline OSCC. ANIMALS: Eight cats with OSCC were prospectively treated with zoledronate and conventional treatment modalities. METHODS: In vitro, zoledronate's effects in modulating soluble vascular endothelial growth factor (VEGF) secretion and receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) expression were investigated in a feline OSCC cell line (SCCF1). In vivo, basal serum C-telopeptide (CTx) concentrations were compared among normal and OSCC-bearing cats, and the biologic effects of zoledronate administration in cats with naturally occurring OSCC were quantified by serially assessing circulating serum VEGF and CTx concentrations. RESULTS: In vitro, zoledronate concentrations greater than 3 microM reduce soluble VEGF secretion in the SCCF1 cell line. The expression of RANKL in the SCCF1 cell line was also modulated by zoledronate, with low concentrations (3 microM) decreasing but higher concentrations (30 microM) increasing RANKL expression in comparison with untreated cells. In vivo, cats with bone-invasive OSCC had greater serum CTx concentrations in comparison with geriatric, healthy controls. Treatment with zoledronate rapidly decreased circulating serum VEGF and CTx concentrations in cats with spontaneously occurring OSCC. CONCLUSIONS AND CLINICAL IMPORTANCE: Zoledronate exerts in vitro and in vivo effects that may favor the slowing of tumor growth and pathologic bone turnover associated with OSCC.