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PMID: 12438453 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 110 ·No. 10 ·2002-11-00 ·Pages 1559-72

Gallwitz WE, Guise TA, Mundy GR

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.

MeSH Terms
Animals Bone Neoplasms/metabolism Breast Neoplasms/drug therapy,genetics,metabolism Cytokines/biosynthesis Female Gene Expression/drug effects Guanine Nucleotides/pharmacology Guanosine/analogs & derivatives,pharmacology Humans Hypercalcemia/metabolism,prevention & control Mice Mice, Nude Neoplasm Transplantation Neoplasms/drug therapy,genetics,metabolism Osteolysis/metabolism,prevention & control Paraneoplastic Endocrine Syndromes/genetics,metabolism,prevention & control Parathyroid Hormone-Related Protein Peptide Hormones/genetics,metabolism Promoter Regions, Genetic Thioguanine/pharmacology Thionucleosides/pharmacology Transplantation, Heterologous Tumor Cells, Cultured
Chemicals
Cytokines Guanine Nucleotides PTHLH protein, human Parathyroid Hormone-Related Protein Peptide Hormones Thionucleosides Guanosine 6-thioguanosine Thioguanine
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Gallwitz Wolfgang E
OsteoScreen Ltd., San Antonio, Texas 78229, USA. [email protected]
Guise Theresa A
Mundy Gregory R
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI11936
Email
[email protected]
Published
2002-11-00
Pages
1559-72
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151806
Subset
IM
Grants
NCI NIH HHS · P01 CA040035 · United States
NCI NIH HHS · P01CA40035 · United States
Corrections
CommentIn
PMID: 12438435
External Links
PubMed source DOI: 10.1172/JCI11936 PMC Full Text View journal details
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