Hypercalcemia represents one of the important
paraneoplastic syndromes affecting morbidity and mortality of
cancer patients. We and others have demonstrated that
vitamin D analogs with little calcemic activities suppress the transcription of the
parathyroid hormone-related peptide (
PTHrP) gene, a major humor responsible for
cancer hypercalcemia, and thereby prevent the development of hypercalcemic syndrome. The present study was undertaken: to compare the therapeutic efficacy of a
vitamin D analog,
22-oxa-1,25-dihydroxyvitamin D3 (OCT), and a
bisphosphonate (disodium 3-amino-1-hydroxypropylidene-1,1-
bisphosphonate pentahydrate [
AHPrBP]), an inhibitor of osteoclastic
bone resorption, on
cancer-induced
hypercalcemia; and to see if the effect could be enhanced by combination treatment, using a nude mouse model implanted with a human pancreas
carcinoma (FA-6). After a single
intravenous administration, OCT (5 microg/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 effect. Although
AHPrBP lost its efficacy after repeated
injections, OCT was still effective after the third administration. The
therapeutic effect of OCT in
cancer hypercalcemia was observed in four other human
tumors, 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 circulation. Treatment with OCT resulted in a decrease in circulating
PTHrP levels by approximately 50% in two representative models. However, the mechanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of
PTHrP production, suppression of excessive
bone 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 preventing
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 that OCT may be useful, either as a single agent or in combination with
bisphosphonates, for the treatment of
cancer-associated
hypercalcemia and
cachexia.