thioguanine-anhydrous and Bone-Neoplasms

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.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cytokines; Female; Gene Expression; Guanine Nucleotides; Guanosine; Humans; Hypercalcemia; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Osteolysis; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone-Related Protein; Peptide Hormones; Promoter Regions, Genetic; Thioguanine; Thionucleosides; Transplantation, Heterologous; Tumor Cells, Cultured

The results obtained with very intensive treatment in previously untreated patients early in the disease are encouraging, and we hope will change the philosophy of most investigators that even in far advanced disease such as those with marrow metastases or multiple primary sites, one can still obtain complete regression at all tumour sites within 1 to 1 1/2 months from onset of therapy by combined treatment with multiple chemotherapeutic agents and radiation therapy to one or more sites.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Bone Neoplasms; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Female; Humans; Hydroxyurea; Leukemia; Leukemia, Lymphoid; Lymph Nodes; Lymphoma; Male; Mediastinal Neoplasms; Methotrexate; Nasopharyngeal Neoplasms; Ovarian Neoplasms; Skin Neoplasms; Stomach Neoplasms; Thioguanine; Vincristine