PTH-related peptide (PTHrP) mediates the syndrome of humoral hypercalcemia of 
malignancy, a frequent complication of squamous cell carcinomas of the lung. 
This study was undertaken to determine whether 1,25-dihydroxyvitamin D3 
[1,25-(OH)2D3] and two nonhypercalcemic analogs, EB1089 and 22-oxa-1,25-(OH)2D3 
(22-oxacalcitriol), suppress serum- and epidermal growth factor (EGF)-induced 
PTHrP gene expression in a human lung squamous cancer cell line, NCI H520. PTHrP 
expression was up-regulated by serum and EGF in a concentration- and 
time-dependent manner. Nuclear run-on analysis showed that this induction was 
mediated via a transcriptional mechanism, and that sequences within promoter 1 
were responsible. All three vitamin D3 compounds decreased both basal and serum- 
and EGF-induced steady state PTHrP messenger RNA and secreted peptide levels. 
These effects were again mediated via a transcriptional mechanism through 
sequences within promoter 1. All three vitamin D3 compounds also decreased the 
proliferation of NCI H520 cells in a concentration- and time-dependent manner. 
1,25-(OH)2D3 is hypercalcemic in vivo. However, the noncalcemic analogs EB1089 
and 22-oxa-1,25-(OH)2D3 have therapeutic potential, as they suppress not only 
the basal but also the growth factor-stimulated levels of PTHrP in a cancer cell 
line associated with hypercalcemia.