Guanosine nucleoticles inhibit different syndromes of PTHrP excess caused by human cancers in vivo
Guanosine nucleoticles inhibit different syndromes of PTHrP excess caused by human cancers in vivo
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DOI：
10.1172/jci200211936
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发表时间：
2002-11-01
影响因子：
15.9
通讯作者：
Mundy, GR
中科院分区：
文献类型：
--
作者：
Gallwitz, WE;Guise, TA;Mundy, GR
有两种由肿瘤产生甲状旁腺素相关肽（PTHrP）引起的综合征，即与乳腺癌相关的溶骨性骨病和伴有或不伴有骨转移的恶性肿瘤体液性高钙血症（HHM）。这两种综合征已被实验证明可以被PTHrP的中和抗体抑制。在寻找PTHrP产生或作用的小分子抑制剂中，我们已经鉴定了鸟嘌呤核苷酸类似物作为抑制与这些综合征相关的人肿瘤细胞表达PTHrP的化合物。我们在裸无胸腺小鼠模型，这些化合物减少PTHrP介导的溶骨性病变相关的转移性人乳腺癌细胞，以及由肺鳞状细胞癌过度PTHrP生产引起的高钙血症的程度。这些结果表明PTHrP基因启动子可能是治疗恶性肿瘤骨骼效应的合适靶点。
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.