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- Author or Editor: Timothy M. Fan x
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Abstract
OBJECTIVE To characterize spatial release of platinum from carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads by use of an agarose tissue phantom.
SAMPLE 3-mm-diameter beads (n = 60) containing 4.6 mg of carboplatin (2.4 mg of platinum)/bead.
PROCEDURES 18 L of 1% agarose was prepared and poured into 36 containers (10 × 10 × 10 cm), each of which was filled half full (0.5 L/container). After the agarose solidified, 1, 3, 6, or 10 CI-CSH beads were placed on the agar in defined patterns. An additional 36 blocks of agar (0.5 L/block) were placed atop the beads, positioning the beads in the center of 1 L of agar. The experiment was replicated 3 times for each bead pattern for 24, 48, and 72 hours. At these times, representative agarose blocks were sectioned in the x-, y-, and z-planes and labeled in accordance with their positions in shells radiating 1, 2, 3, 4, and 5 cm from the center of the blocks. Agarose from each shell was homogenized, and a sample was submitted for platinum analysis by use of inductively coupled plasma–mass spectroscopy.
RESULTS Platinum diffused from CI-CSH beads at predicted anticancer cytotoxic concentrations for 2 to 5 cm.
CONCLUSIONS AND CLINICAL RELEVANCE Results provided information regarding the spatial distribution of platinum expected to occur in vivo. Agarose may be used as a diffusion model, mimicking the characteristics of subcutaneous tissues. Measured platinum concentrations might be used to guide patterns for implantation of CI-CSH beads in animals with susceptible neoplasms.
Abstract
In this article, which is part of the Currents in One Health series, principles of immunotherapeutics are discussed and their clinical exploration in dogs reviewed with emphasis on their translatability for improving treatment of commonly diagnosed cancers. With increasing longevity and sustained quality of life in pet dogs through dietary, environmental awareness, and preventative medical practices, the geriatric pet population has continued to steadily grow and, consequently, so have age-related pathologies. Not surprisingly, cancer is the most common cause of mortality in elderly dogs, accounting for 1 in 4 deaths in dogs > 10 years of age. Importantly, some cancer types that arise spontaneously in pet dogs are similar to cancers afflicting people. The shared clinical and biological behaviors of certain cancers observed in pet dogs and people underscore the opportunity to leverage comparative oncology studies, which can accelerate the validation and clinical implementation of innovative therapies that can benefit pet dogs and ultimately guide these strategies toward clinical practice in people too. In the era of immunotherapy, the inclusion of pet dogs that develop cancers under an intact immune system affords a unique and high-value opportunity to study the evolving nature of cancers shaped by immunosurveillance pressures. Complementing these discovery efforts and through a comparative oncology approach, the exploration and clinical validation of novel immunotherapeutic strategies in pet dogs can be foundational for defining the safety and immune-activating potential of new anticancer immune approaches that hold promise to transform cancer treatment in both pets and people alike.
Abstract
Objective—To determine concentrations of receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) in equine chondrocytes and synoviocytes and to quantify changes in the OPG:RANKL ratio in response to exogenous factors.
Sample Population—Samples of articular cartilage and synovium with grossly normal appearance obtained from metacarpophalangeal and metatarsophalangeal joints of 5 adult (1- to 8-year-old) horses.
Procedures—Cell cultures of chondrocytes and synoviocytes were incubated with human recombinant interleukin-1B (hrIL-1β; 10 ng/mL), lipopolysaccharide (LPS; 10 μg/mL), or dexamethasone (100nM) for 48 hours. Negative control cultures received no treatment. Cells and spent media were assayed for RANKL and OPG concentrations by use of western blot and immunocytochemical analyses. Spent media were also assayed for OPG concentration by use of an ELISA.
Results—RANKL and OPG were expressed in equine chondrocytes and synoviocytes in vitro. Cell-associated RANKL and OPG concentrations were not impacted by exogenous factors. Soluble RANKL release into media was significantly increased by hrIL-1β in chondrocyte but not in synoviocyte cultures. Soluble OPG release into media was significantly increased by hrIL-1β and LPS in chondrocyte but not in synoviocyte cultures. The soluble OPG:RANKL ratio was significantly increased by LPS in chondrocyte cultures. Dexamethasone decreased OPG expression in synoviocytes.
Conclusions and Clinical Relevance—RANKL and OPG proteins were expressed in equine articular cells. Release of these proteins may affect osteoclastogenesis within adjacent subchondral bone. Thus, RANKL and OPG may have use as biomarkers and treatment targets in horses with joint disease.
Abstract
Objective—To describe clinical outcome of dogs with mast cell tumors (MCTs) arising from the oral mucosa, oral mucocutaneous junction, or perioral region of the muzzle and evaluate the potential role of the chemokine receptor type 7 (CCR7) in the biological behavior of these tumors.
Design—Retrospective case series.
Animals—44 dogs with MCTs of the oral mucosa (n = 14), oral mucocutaneous junction (19), or perioral region of the muzzle (11).
Procedures—Medical records were reviewed for information on signalment, regional metastasis, treatments, cause of death, and survival time. Twenty of the 44 cases had stored histologic samples available for immunohistochemical staining for CCR7
Results—For all dogs, median survival time was 52 months. Twenty-six (59%) dogs had regional lymph node metastasis on admission. Median survival time for dogs with lymph node metastasis was 14 months, whereas median survival time was not reached for dogs without lymph node metastasis. Intensity of staining for CCR7 was not significantly associated with the presence of regional lymph node metastasis or survival time.
Conclusions and Clinical Relevance—Results suggested that in dogs with MCTs arising from the oral mucosa, oral mucocutaneous junction, or perioral region of the muzzle, the presence of regional lymph node metastasis at the time of diagnosis was a negative prognostic factor. However, prolonged survival times could be achieved with treatment. In addition, CCR7 expression in the primary tumor was not significantly associated with the presence of regional lymph node metastasis or survival time.
Abstract
OBJECTIVE To determine the pharmacokinetics of orally administered rapamycin in healthy dogs.
ANIMALS 5 healthy purpose-bred hounds.
PROCEDURES The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography–tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses.
RESULTS Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose.
CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.
Abstract
OBJECTIVE
To evaluate feline injection site-associated sarcoma (FISAS) and oral squamous cell carcinoma (FOSCC) cells in 3-D hydrogel-based cell cultures to determine chemosensitivity to carboplatin at concentrations comparable to those eluted from carboplatin-impregnated calcium sulfate hemihydrate (C-ICSH) beads.
SAMPLE
2 immortalized cell lines, each from a histologically confirmed primary FISAS and FOSCC.
PROCEDURES
Hydrogels (10% wt/vol) were formed via UV exposure from methacrylamide-functionalized gelatin dissolved in PBSS. For each cell line, approximately 100,000 cells were encapsulated per hydrogel. Three cell-seeded 3-D hydrogels were evaluated for each carboplatin concentration (0, 150, 300, 450, and 600 µM) across 3 experiments. Drug efficacy was assessed by luminescence assay 72 hours after treatment. Growth of tumor cells treated with 300 µM or 600 µM carboplatin was evaluated using live-cell morphology imaging and confocal microscopy at 3, 7, and 14 days after treatment.
RESULTS
Mean half-maximal inhibitory concentration (IC50) values for FISAS and FOSCC cells ranged from 123 to 171 µM and 155 to 190 µM, respectively, based on luminescence assay. Viability at 3, 7, and 14 days for both cell lines at 300 µM carboplatin was 50%, 25%, and 5% and at 600 µM carboplatin was 25%, 10%, and < 5%.
CLINICAL RELEVANCE
3-D hydrogel cell culture systems supported growth of feline tumor cells for determination of in vitro chemosensitivity. IC50s of each cell line were within the range of carboplatin concentrations eluted from C-ICSH beads. Cells from FISAS and FOSCC cell lines treated with carboplatin showed dose-dependent and time-dependent decreases in viability.
