Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo

Wolfgang E. Gallwitz, Theresa A. Guise, Gregory R. Mundy

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

There are two well-described syndromes caused by tumor production of parathyroid hormone-related peptide (PTHrP), namely osteolytic bone disease associated with breast cancer and humoral hypercalcemia of malignancy (HHM) that occurs with or without bone metastasis. Both syndromes have been shown experimentally to be inhibited by neutralizing antibodies to PTHrP. In a search for small-molecule inhibitors of PTHrP production or effects, we have identified guanine-nucleotide analogs as compounds that inhibit PTHrP expression by human tumor cells associated with these syndromes. We show in nude athymic murine models that these compounds reduce PTHrP-mediated osteolytic lesions associated with metastatic human breast-cancer cells as well as the degree of hypercalcemia caused by excessive PTHrP production by a squamous-cell carcinoma of the lung. These results suggest that the PTHrP gene promoter may be a suitable target for treating the skeletal effects of malignancy.

Original languageEnglish (US)
Pages (from-to)1559-1572
Number of pages14
JournalJournal of Clinical Investigation
Volume110
Issue number10
DOIs
StatePublished - Nov 2002

ASJC Scopus subject areas

  • Medicine(all)

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