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

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

Research output: Contribution to journalArticle

60 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Parathyroid Hormone-Related Protein
Guanosine
Nucleotides
Neoplasms
Breast Neoplasms
Guanine Nucleotides
Bone Diseases
Hypercalcemia
Neutralizing Antibodies
Squamous Cell Carcinoma
Neoplasm Metastasis
Bone and Bones
Lung
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo. / Gallwitz, Wolfgang E.; Guise, Theresa; Mundy, Gregory R.

In: Journal of Clinical Investigation, Vol. 110, No. 10, 11.2002, p. 1559-1572.

Research output: Contribution to journalArticle

@article{c08c05027a8b4e9c93b12804500f5a9c,
title = "Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo",
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.",
author = "Gallwitz, {Wolfgang E.} and Theresa Guise and Mundy, {Gregory R.}",
year = "2002",
month = "11",
doi = "10.1172/JCI200211936",
language = "English (US)",
volume = "110",
pages = "1559--1572",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",

}

TY - JOUR

T1 - Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo

AU - Gallwitz, Wolfgang E.

AU - Guise, Theresa

AU - Mundy, Gregory R.

PY - 2002/11

Y1 - 2002/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0036853893&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036853893&partnerID=8YFLogxK

U2 - 10.1172/JCI200211936

DO - 10.1172/JCI200211936

M3 - Article

VL - 110

SP - 1559

EP - 1572

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 10

ER -