Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo.
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.
Gallwitz
Wolfgang E
WE
OsteoScreen Ltd., San Antonio, Texas 78229, USA. gallwitz@osteoscreen.com
Guise
Theresa A
TA
Mundy
Gregory R
GR
D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006150:Guanine Nucleotides / Q000494:pharmacology*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010014:Osteolysis / Q000378:metabolism / Q000517:prevention & control; D009384:Paraneoplastic Endocrine Syndromes / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013866:Thioguanine / Q000494:pharmacology; D013872:Thionucleosides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D016207:Cytokines; D006150:Guanine Nucleotides; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D013872:Thionucleosides; D006151:Guanosine; C005783:6-thioguanosine; D013866:Thioguanine