A hypercalcemic nude rat model that completely mimics human syndrome of humoral hypercalcemia of malignancy

Abstract

Tumors causing humoral hypercalcemia of malignancy (HHM) were implanted to athymic nude rats. In one of these rat models transplanted with uterine cancer (UCC), a complete reproduction of human HHM syndrome was achieved: hypercalcemia, hypophosphatemia with increased urinary phosphate and cyclic AMP excretion, and suppressed serum 1,25-dihydroxy-vitamin D (1,25(OH)2D) level. In another hypercalcemic nude rat model implanted with oral cavity cancer (OCC), all the features were similar except for markedly elevated serum 1,25(OH)2D. Hypercalcemia disappeared by surgical removal of the tumors in both models, confirming the humoral mechanisms for causing these features. Furthermore, in UCC tumor-bearing rats, hypophosphatemia, increased renal phosphate excretion, and reduced serum 1,25(OH)2D concentration were already present when these rats were only marginally hypercalcemic. These results raise the possibility that the changes in renal tubular phosphate handling and vitamin D metabolism in HHM are not secondary to hypercalcemia but are due to direct effects of the humoral factor(s) that cause this syndrome. Extracts of both tumors exhibited stimulation of cyclic AMP production in osteoblastlike cells, UMR 106, which could be almost completely inhibited by parathyroid hormone (PTH) antagonist, human PTH(3-34). By comparing the nature and characteristics of humoral factor(s) from UCC and OCC models, mechanisms responsible for causing these abnormalities can be explored. Thus, these nude rat models can be useful for elucidating the underlying mechanism of the development of HHM.

Parathyroid hormone–related protein (PTHrP) as a causative factor of cancer‐associated wasting: Possible involvement of PTHrP in the repression of locomotor activity in rats bearing human tumor xenografts

“…Tumor resection was performed under anesthesia with sodium pentobarbital. 11 Tumor resection and administration of anti-PTHrP MAb (3 mg/kg) or saline were carried out 49 days after tumor transplantation; all rats were killed 59 days after tumor transplantation, to measure body weight, indicated tissue weights and indicated parameters. Fat and muscle contents were determined by measuring the weights of the epididymal adipose tissue and gastrocnemius muscle, as described.…”

Conflicting actions of parathyroid hormone-related protein and serum calcium as regulators of 25-hydroxyvitamin D(3)-1 alpha-hydroxylase expression in a nude rat model of humoral hypercalcemia of malignancy

“…To date, a number of animal models have been developed which mimic the pathological state of patients with HHM (Ikeda et al 1988, Nagai et al 1998. However, serum levels of 1,25(OH) 2 D are not suppressed in most of these models, although hypercalcemia occurs associated with elevated levels of PTHrP (Ikeda & Ogata 1995).…”

“…Because administration of synthetic peptides for PTHrP(1-34) or PTHrP(1-36) increases the plasma 1,25(OH) 2 D concentration as does the administration of PTH(1-34) (Fraher et al 1992, factors other than overproduction of PTHrP have been postulated as the cause of low 1,25(OH) 2 D levels. However, such factors have not been identified yet, partly due to the lack of appropriate animal models; animals bearing human tumors producing PTHrP generally do not exhibit a reduction in serum 1,25(OH) 2 D levels (Ikeda et al 1988, Ikeda & Ogata 1995.…”

Production of parathyroid hormone-related protein in tumour xenografts in nude mice presenting with hypercalcaemia

“…In the five extracts of tumours associated with hypercalcaemia, BIO-PTHrP was significantly elevated ranging from 160 to 380% above basal. Since the bioactivities were measured at the bottom portion of the (Gkonos et al, 1984;Weir et al, 1988;Kukreja et al, 1988;Ikeda et al, 1988). However, Mehdizadeh et al (1989) (Honda et al, 1988a;Budayr et al, 1989a;Burtis et al, 1990;Tsuchihashi et al, 1990).…”