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  • Author or Editor: Cheryl E. Balkman x
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Abstract

Objective—To determine the effects of lycopene with and without concurrent chemotherapeutic treatment on growth and apoptosis of canine osteosarcoma cells.

Sample Population—Cell cultures of 3 established canine osteosarcoma cell lines (D17, OS 2.4, and HMPOS).

Procedures—Growth curve kinetics and cell cytotoxicosis for various treatment combinations were assessed by use of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Additionally, cell cycle kinetics and colony-forming soft agar assays were performed to determine the influences of lycopene on the cell cycle and anchorageindependent growth. Western immunoblotting of HMPOS cells was performed to examine signaling and apoptotic pathways implicated in lycopene-induced apoptosis.

Results—Lycopene alone caused mild to pronounced attenuation of cell proliferation of all 3 cell lines as well as apoptosis in HMPOS cells but did not interfere with cell death in response to doxorubicin. Soft agar anchorage-independent growth assays revealed complete inhibition of cell proliferation in 2 of 3 osteosarcoma cell lines. Further investigation into the apoptotic response revealed activation of mitochondrial-induced apoptosis primarily through expression of truncated Bid and a decrease in protein kinase B (ie, AKT) phosphorylation.

Conclusions and Clinical Relevance—Results suggested that lycopene may be beneficial during treatment of osteosarcomas. Lycopene did not negatively or positively affect survival of osteosarcoma cells during doxorubicin treatment and independently induced apoptosis in the HMPOS cell line. These findings warrant further in vitro and in vivo studies into the use of this natural compound as an adjuvant antiproliferative, proapoptotic treatment in dogs with osteosarcoma.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine the maximum tolerated dose and characterize the pharmacokinetic disposition of an orally administered combination of docetaxel and cyclosporin A (CSA) in dogs with tumors.

Animals—16 client-owned dogs with metastatic or advanced-stage refractory tumors.

Procedures—An open-label, dose-escalation, singledose, phase I study of docetaxel administered in combination with a fixed dose of CSA was conducted. Docetaxel (at doses of 1.5, 1.625, or 1.75 mg/kg) and CSA (5 mg/kg) were administered concurrently via gavage twice during a 3-week period. Plasma docetaxel concentrations were quantified by use of high-performance liquid chromatography, and pharmacokinetic disposition was characterized by use of noncompartmental analysis. Dogs' clinical signs and results of hematologic and biochemical analyses were monitored for evidence of toxicosis.

Results—No acute hypersensitivity reactions were observed after oral administration of docetaxel. Disposition of docetaxel was dose independent over the range evaluated, and pharmacokinetic variables were similar to those reported in previous studies involving healthy dogs, with the exception that values for clearance were significantly higher in the dogs reported here. The maximum tolerated dose of docetaxel was 1.625 mg/kg. Gastrointestinal signs of toxicosis were dose limiting.

Conclusions and Clinical Relevance—The absence of myelosuppression suggested that the docetaxelCSA combination may be administered more frequently than the schedule used. Further studies are warranted to evaluate combination treatment administered on a biweekly schedule in dogs with epithelial tumors.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To evaluate 3 methods for measuring urine bile acids (UBA) and compare their diagnostic performance with that of the serum bile acids (SBA) test and other routine screening tests in dogs with hepatic disorders.

Design—Prospective study.

Animals—15 healthy dogs, 102 dogs with hepatic disorders, and 9 dogs with clinical signs of hepatic disorders that were found to have nonhepatic disorders.

Procedures—Blood and urine samples were collected from sick dogs and healthy dogs for serum biochemical analyses, and determination of concentrations of SBA and UBA. Urine samples were obtained from 15 healthy dogs to establish an upper cutoff value for UBA concentrations. The UBA were measured by use of a quantitative-linked enzymatic colorimetric method. Three analytical modifications were evaluated; 1 quantified only urine sulfated bile acids (USBA), 1 only urine nonsulfated bile acids (UNSBA), and 1 quantified both (USBA plus UNSBA). The UBA values were standardized with the urine creatinine concentration.

Results—The UNSBA-to-creatinine ratio and USBA plus UNSBA-to-creatinine ratio tests had the best diagnostic performance of the UBA tests; each had a substantially higher specificity, slightly higher positive predictive value, slightly lower negative predictive value, and lower sensitivity than the SBA test. These UBA-to-creatinine values were positively correlated with SBA values. The USBA-to-creatinine ratio had poor sensitivity, indicating a low rate of bile acid sulfation in dogs.

Conclusions and Clinical Relevance—The UBA can be measured in dogs with sufficient repeatability and accuracy for clinical application. The UNSBA-to-creatinine ratio and USBA plus UNSBA-to-creatinine ratio identified dogs with hepatic disorders nearly as well as the SBA test. (J Am Vet Med Assoc 2003;222: 1368–1375)

Restricted access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To characterize oral bioavailability and pharmacokinetic disposition of etoposide when the IV formulation was administered orally to dogs.

Animals—8 tumor-bearing dogs.

Procedures—An open-label, single-dose, 2-way crossover study was conducted. Dogs were randomly assigned to initially receive a single dose of etoposide (50 mg/m2) IV or PO. A second dose was administered via the alternate route 3 to 7 days later. Medications were administered before IV administration of etoposide to prevent hypersensitivity reactions. Oral administration of etoposide was prepared by reconstituting the parenteral formulation with 0.9% NaCl solution and further diluting the reconstituted mixture 1:1 with a sweetening agent. Plasma samples were obtained after both treatments. Etoposide concentrations were measured with a high-performance liquid chromatography assay, and plasma etoposide concentration–time profiles were analyzed by use of noncompartmental methods.

Results—4 dogs had hypersensitivity reactions during IV administration of etoposide. No adverse effects were detected after oral administration. Plasma etoposide concentrations were undetectable in 2 dogs after oral administration. Oral administration of etoposide resulted in significantly lower values for the maximum plasma concentration and the area under the plasma etoposide concentration-versus-time curve, compared with results for IV administration. Oral bioavailability of etoposide was low (median, 13.4%) and highly variable among dogs (range, 5.7% to 57.3%).

Conclusions and Clinical Relevance—Vehicle-related toxicosis can limit the IV administration of etoposide in dogs. The parenteral formulation of etoposide can be safely administered orally to dogs, but routine use was not supported because of low and variable oral bioavailability in this study.

Full access
in American Journal of Veterinary Research