EFFECT OF COMBINATION TREATMENT WITH A VITAMIN-D ANALOG (OCT) AND A BISPHOSPHONATE (AHPRBP) IN A NUDE-MOUSE MODEL OF CANCER-ASSOCIATED HYPERCALCEMIA

Hypercalcemia represents one of the important paraneoplastic syndromes affecting morbidity and mortality of cancer patients. We and others h ave demonstrated that vitamin D analogs with little calcemic activitie s suppress the transcription of the parathyroid hormone-related peptid e (PTHrP) gene, a major humor responsible for cancer hypercalcemia, an d thereby prevent the development of hypercalcemic syndrome. The prese nt study was undertaken: to compare the therapeutic efficacy of a vita min D analog, 22-oxa-1,25-dihydroxyvitamin D-3 (OCT), and a bisphospho nate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahy drate [AHPrBP]), an inhibitor of osteoclastic bone resorption, on canc er-induced hypercalcemia; and to see if the effect could be enhanced b y combination treatment, using a nude mouse model implanted with a hum an pancreas carcinoma (FA-6). After a single intravenous administratio n, OCT (5 mu g/kg of body weight [BW]) was as effective as AHPrBP (10 mg/kg of BW) in lowering blood ionized calcium levels in tumor-bearing nude mice, and their combination further enhanced the therapeutic eff ect. Although AHPrBP lost its efficacy after repeated injections, OCT was still effective after the third administration. The therapeutic ef fect of OCT in cancer hypercalcemia was observed in four other human t umors, including another pancreas carcinoma (PAN-7), two squamous cell carcinomas of the lung (KCC-C1 and LC-6), and a squamous carcinoma of the pharynx (PHA-1), all of which elaborated PTHrP into the circulati on. Treatment with OCT resulted in a decrease in circulating PTHrP lev els by approximately 50% in two representative models. However, the me chanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of PTHrP production, suppression of excessive bo ne resorption, and an antitumor activity. OCT also markedly inhibited the body weight loss with tumor growth, while AHPrBP, which exhibited a similar antihypercalcemic effect, was less effective than OCT in pre venting cachexia. The anticachectic activity of their combination did not exceed that of OCT alone, suggesting a hypercalcemia-dependent as well as an independent mechanism of cancer cachexia. It is concluded t hat OCT may be useful, either as a single agent or in combination with bisphosphonates, for the treatment of cancer-associated hypercalcemia and cachexia.