Endo K, Katsumata K, Iguchi H, Kubodera N, Teramoto T, Ikeda K, Fujita T, Ogata E
Pharmaceutical Research Laboratory, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
J Bone Miner Res. 1998 Sep;13(9):1378-83. doi: 10.1359/jbmr.1998.13.9.1378.
Hypercalcemia represents one of the important paraneoplastic syndromes affecting morbidity and mortality of cancer patients. We and others have demonstrated that vitamin D analogs with little calcemic activities suppress the transcription of the parathyroid hormone-related peptide (PTHrP) gene, a major humor responsible for cancer hypercalcemia, and thereby prevent the development of hypercalcemic syndrome. The present study was undertaken: to compare the therapeutic efficacy of a vitamin D analog, 22-oxa-1,25-dihydroxyvitamin D3 (OCT), and a bisphosphonate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate [AHPrBP]), an inhibitor of osteoclastic bone resorption, on cancer-induced hypercalcemia; and to see if the effect could be enhanced by combination treatment, using a nude mouse model implanted with a human pancreas carcinoma (FA-6). After a single intravenous administration, OCT (5 microg/kg of body weight [BW]) was as effective as AHPrBP (10 mg/kg of BW) in lowering blood ionized calcium levels in tumor-bearing nude mice, and their combination further enhanced the therapeutic effect. Although AHPrBP lost its efficacy after repeated injections, OCT was still effective after the third administration. The therapeutic effect of OCT in cancer hypercalcemia was observed in four other human tumors, including another pancreas carcinoma (PAN-7), two squamous cell carcinomas of the lung (KCC-C1 and LC-6), and a squamous carcinoma of the pharynx (PHA-1), all of which elaborated PTHrP into the circulation. Treatment with OCT resulted in a decrease in circulating PTHrP levels by approximately 50% in two representative models. However, the mechanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of PTHrP production, suppression of excessive bone resorption, and an antitumor activity. OCT also markedly inhibited the body weight loss with tumor growth, while AHPrBP, which exhibited a similar antihypercalcemic effect, was less effective than OCT in preventing cachexia. The anticachectic activity of their combination did not exceed that of OCT alone, suggesting a hypercalcemia-dependent as well as an independent mechanism of cancer cachexia. It is concluded that OCT may be useful, either as a single agent or in combination with bisphosphonates, for the treatment of cancer-associated hypercalcemia and cachexia.
高钙血症是影响癌症患者发病率和死亡率的重要副肿瘤综合征之一。我们和其他研究人员已证明，具有低血钙活性的维生素D类似物可抑制甲状旁腺激素相关肽（PTHrP）基因的转录，PTHrP是导致癌症高钙血症的主要体液因子，从而预防高钙血症综合征的发生。进行本研究的目的是：比较一种维生素D类似物22-氧杂-1,25-二羟基维生素D3（OCT）和一种双膦酸盐（3-氨基-1-羟基亚丙基-1,1-双膦酸五水合二钠[AHPrBP]，一种破骨细胞骨吸收抑制剂）对癌症诱发的高钙血症的治疗效果；并观察联合治疗是否能增强疗效，采用植入人胰腺癌（FA-6）的裸鼠模型进行研究。单次静脉给药后，OCT（5微克/千克体重[BW]）在降低荷瘤裸鼠血离子钙水平方面与AHPrBP（10毫克/千克体重）效果相当，二者联合使用可进一步增强治疗效果。尽管重复注射后AHPrBP失去疗效，但第三次给药后OCT仍有效。在另外四种人类肿瘤中也观察到了OCT对癌症高钙血症的治疗效果，包括另一种胰腺癌（PAN-7）、两种肺鳞状细胞癌（KCC-C1和LC-6）以及一种咽鳞状细胞癌（PHA-1），所有这些肿瘤都会将PTHrP释放到循环中。在两个代表性模型中，用OCT治疗可使循环中PTHrP水平降低约50%。然而，OCT抗高钙血症作用的潜在机制似乎较为复杂，涉及抑制PTHrP生成抑制过度的骨吸收以及抗肿瘤活性。OCT还显著抑制了肿瘤生长导致的体重减轻，而具有类似抗高钙血症作用的AHPrBP在预防恶病质方面不如OCT有效。二者联合的抗恶病质活性不超过单独使用OCT的效果，提示癌症恶病质存在高钙血症依赖性及非依赖性机制。结论是，OCT无论是单独使用还是与双膦酸盐联合使用，都可能对治疗癌症相关的高钙血症和恶病质有用。
