Effects of 1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃] and Its Analogues (EB1089 and Analog V) on Canine Adenocarcinoma (CAC-8) in Nude Mice

Abstract

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...

Vitamin D receptor expression in canine mammary gland and relationship with clinicopathological parameters and progesterone/oestrogen receptors

“…In canine species, the VDR expression has been shown on the majority of the mast cell tumours and osteosarcomas . Vitamin D metabolites have been shown to have in vitro anti cancerous effects on canine cancer cell lines, with some evidence of in vivo efficacy …”

Vitamin D metabolism in dogs and cats and its relation to diseases not associated with bone metabolism

“…In addition, an increased relative risk (RR) for cancer was observed as serum 25(OH)D levels decreased; therefore, the RR of cancer for 25(OH)D below 40 ng/ml of all-cancer group and of HAS group were 3.9 and 4.1, respectively, compared with that of the control group. In contrast,Willcox, Hammett-Stabler, and Hauck (2016) found no difference in serum concentrations of 25(OH)D in 20 dogs affected by osteosarcoma, compared with a control group matched for age and body weight.Studies have demonstrated in vitro antineoplastic effects of calcitriol for various types of canine tumours, including osteosarcoma(Barroga, Kadosawa, Okumura, & Fujinaga, 1999), squamous cell carcinoma(Kunakornsawat et al, 2001), prostatic epithelial tumour(Kunakornsawat et al, 2004), anal sac adenocarcinoma(Kunakornsawat et al, 2002), mammary gland cancer(Rassnick et al, 2008) and mastocytoma(Malone et al, 2010). These findings reinforce the hypothesis that low concentrations of vitamin D may increase the risk of developing cancer.…”

“…Wakshlag et al (2011) evaluated the relationship between serum concentrations of 25(OH)D and mastocytoma in Labrador Retrievers.In total, 33 animals affected by this disease were evaluated and compared with a control group that was composed of 54 healthy animals, and lower serum concentrations 25(OH)D were observed in dogs with mastocytoma.In another study conducted bySelting et al (2016), the 25(OH) D serum concentrations from a group of healthy dogs (control group; n = 282) were compared to 25(OH)D serum concentrations from a group of dogs with splenic malignancies (all-cancer group; n = 40) and with another group of dogs with benign neoplasms (benign group; n = 22). In contrast,Willcox, Hammett-Stabler, and Hauck (2016) found no difference in serum concentrations of 25(OH)D in 20 dogs affected by osteosarcoma, compared with a control group matched for age and body weight.Studies have demonstrated in vitro antineoplastic effects of calcitriol for various types of canine tumours, including osteosarcoma(Barroga, Kadosawa, Okumura, & Fujinaga, 1999), squamous cell carcinoma(Kunakornsawat et al, 2001), prostatic epithelial tumour(Kunakornsawat et al, 2004), anal sac adenocarcinoma(Kunakornsawat et al, 2002), mammary gland cancer(Rassnick et al, 2008) and mastocytoma(Malone et al, 2010). The control group presented higher 25(OH)D serum concentrations when compared to all other groups.…”

Beyond the skeleton: the role of vitamin D in companion animal health

“…1,25 dihydroxyvitamin D has been shown to have in vitro anti cancerous effects on other canine cancer cell lines, with some evidence of in vivo efficacy (Kunakornsawat et al . , Kaewsakhorn et al . , Rassnick et al .…”