This study was conducted to evaluate the pharmacokinetic characteristics of vincristine and their correlation with its clinical effects in dogs with transmissible venereal tumor (TVT). Dogs with TVT were intravenously administered vincristine sulfate at a dose of 0.7 mg/m2 of body surface area. Blood samples were collected starting from 5 min to 48 hr after drug administration. The plasma concentration of vincristine was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of vincristine were characterized using a two-compartmental pharmacokinetic model. The volume of distribution, distribution half-life, elimination half-life and plasma clearance were 0.660 ± 0.210 l/kg, 21.5 ± 6.90 min, 47.6 ± 14.2 min and 0.010 ± 0.001 l/min/kg, respectively. Tumor regression was determined at weekly interval by a physical examination and histopathological analysis. In our study, three to eight administrations of vincristine at a dose of 0.7 mg/m2 were able to induce a complete tumor regression without any evidence of gross lesion of disease. Therefore, this investigation provides the pharmacokinetic characteristics of vincristine in dogs with TVT, which may be used as an integration tool to gain a better understanding of the disposition properties of the drug and the correlation of these properties with the drug’s clinical effects. In addition, we validated the LC-MS/MS method and found that it is suitable for the pharmacokinetic study of vincristine in dog plasma.

Recently the active form of vitamin D, 1a,25-dihydroxyvitamin D 3 , [1,25(OH) 2 D 3 ] and its synthetic analogues have been shown to exert anti-tumor effects both in vitro and in vivo. [1][2][3][4][5] As summarized by Johannes et al.,6) many investigations have reported that 1,25(OH) 2 D 3 and its analogues affect tumor cells due to: a) blockade of the cells in the G 1 /G 0 phase and reduction of the number of cells in S phase of cell cycle progression, 7-9) b) induction of apoptosis, 10,11) c) expression and regulation of oncogenes and tumor suppressor genes, [12][13][14] d) interaction with tumor-or stroma-derived growth factors for growth inhibition [e.g. transforming growth factor (TGFb), insulin-like growth factor (IGF)], [15][16][17] and e) induction of differentiation. 18,19) However, most studies have been completed in human tumors with little information available in other species on the effects of 1,25(OH) 2 D 3 and its analogues.This study examined the effects of 1,25(OH) 2 D 3 and its analogues [22,24-diene-24a,26a,27a-trihomo-1a ,25-dihydroxyvitamin D 3 (EB1089) and 1,25-dihydroxy-16-ene-23-yne-vitamin D 3 (analog V)] on the canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy (HHM) in nude mice. Canine adenocarcinoma derived from apocrine glands of the anal sac is commonly associated with cancer-associated hypercalcemia. [20][21][22] HHM is a paraneoplastic syndrome in dogs that significantly contributes to the morbidity and mortality of cancer patients. It is well documented that an autonomous overproduction of parathyroid hormone-related protein (PTHrP) is the principal humoral factor that causes hypercalcemia in dogs with this carcinoma due to increased release of calcium from bone and enhanced reabsorption of calcium in the kidney. 22,23) The inhibitory effect of 1,25(OH) 2 D 3 and its analogues on PTHrP production thus far has been reported on both normal human cells 24,25) and human tumor cells. [26][27][28][29][30] In order to achieve the inhibitory effect of 1,25(OH) 2 D 3 on PTHrP production, high doses and/or prolonged treatment with this potent active vitamin D metabolite most likely will be needed, which has the potential to enhance the hypercalcemia. 1,25(OH) 2 D 3 itself is also an important regulator of bone development, bone metabolism, calcium homeostasis and increases blood calcium. 31) In order to minimize this potential toxic effect, vitamin D analogues have been synthesized with noncalcemic effect. Among these noncalcemic analogues, EB1089 and analog V, have been studied on tumor growth.1,2,32) The effects of these two analogues (EB1089 and analog V) on canine adenocarcinoma model of HHM in nude mice were evaluated in this study. The specific objectives were to determine the effects of 1,25(OH) 2 D 3 and its analogues on tumor growth and body weight, changes in plasma ionized calcium, PTHrP production, bone resorption, and the distribution of the 1,25(OH) 2 D 3 receptor (VDR) on tumors in CAC-8-bearing mice. * To whom correspondence should be addressed...

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Background The anti‐cancer effects of Gynura procumbens leaves extract (GPE) have been reported in various human cancers. However, the anti‐cancer effects and molecular mechanisms of this extract on canine mammary cancer (CMC) have not yet been elucidated. Objectives The main goal of this study was to investigate the anti‐cancer properties of GPE against two CMC cell lines (CHMp‐13a and CHMp‐5b). Methods The GP leaves were extracted with 80% ethanol. Anti‐cancer potentials of GPE on CHMp‐13a and CHMp‐5b cancer cell lines using dimethyl‐2‐thiazolyl‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT), wound healing, transwell migration, and caspase 3/7 activity assays were evaluated. The mRNA expression levels of two oncogenes: epidermal growth factor receptor (EGFR) and twist family bHLH transcription factor 1 (TWIST) and one tumour suppressor gene: phosphatase and tensin homolog (PTEN) in these cell lines were determined by quantitative real‐time PCR (qRT‐PCR). In addition, The EGFR and PTEN protein levels as well as protein kinase B (AKT) and extracellular signal‐regulated kinase 1/2 (ERK1/2) phosphorylation levels expression were also evaluated by western blot analysis. Results The results showed that GPE caused a significant concentration‐ and time‐dependent reduction in cell proliferation of both CHMp‐13a and CHMp‐5b cells, detected by MTT assays. This extract also significantly suppressed cancer cell migration in both cell lines, tested by wound healing and transwell migration assays. Additionally, the increase in caspase 3/7 activity observed in both CMC cell treated with GPE suggests that GPE induced caspase 3/7 dependent apoptosis. Moreover, GPE significantly decreased EGFR mRNA and protein expression levels compared to control in both cell lines in a dose‐dependent manner. Conclusion These findings emphasized that GPE has an in vitro anti‐cancer activity against CMC by inhibiting EGFR signalling pathway. Thus, GPE may serve as an alternative therapy in CMC with high EGFR expression.