Haq M, Kremer R, Goltzman D, Rabbani S A
Department of Medicine, McGill University.
J Clin Invest. 1993 Jun;91(6):2416-22. doi: 10.1172/JCI116475.
We have examined the effects of 1,25 dihydroxyvitamin D3 (1,25[OH]2D3) and a low calcemic analogue EB1089 on parathyroid hormone-related peptide (PTHRP) production and on the development of hypercalcemia in Fischer rats implanted with the Leydig cell tumor H-500. Leydig cell tumors were implanted subcutaneously into male Fischer rats, which received constant infusions intraperitoneally of either 1,25(OH)2D3 (50-200 pmol/24 h), EB1089 (50-400 pmol/24 h), or vehicle for up to 4 wk. A control group of animals received similar infusions without tumor implantation. Plasma calcium, plasma levels of immunoreactive iPTHRP, and tumor PTHRP mRNA levels were determined as well as tumor size, animal body weight, and animal survival time. Non-tumor-bearing animals receiving > 50 pmol/24 h of 1,25(OH)2D3 became hypercalcemic, whereas no significant change in plasma calcium was observed in animals receiving < or = 200 pmol/24 h of EB1089. Tumor-bearing animals receiving vehicle alone or > 50 pmol/24 h of 1,25(OH)2D3 became severely hypercalcemic within 15 d. However, animals treated with low dose 1,25(OH)2D3 and all doses of EB1089 maintained near-normal or normal levels of plasma calcium for up to 4 wk. Additionally, reduced levels of tumor PTHRP mRNA and of plasma iPTHRP were observed compared with controls in both vitamin D- and EB1089-treated rats. Infusion of 50 pmol/24 h of 1,25(OH)2D3 and 200 pmol/24 h of EB1089 significantly reduced tumor volume by the end of experiment. The analogue but not 1,25(OH)2D3 substantially prolonged survival time in tumor-bearing animals with longer survival achieved at the highest dose, 400 pmol/24 h, of EB1089. These studies demonstrate that 1,25(OH)2D3 and a low calcemic vitamin D analogue are potent inhibitors of PTHRP production in vivo. Low calcemic analogues may therefore represent important alternative therapy for malignancy-associated hypercalcemia.
我们研究了1,25-二羟基维生素D3（1,25[OH]2D3）和低血钙类似物EB1089对植入睾丸间质细胞瘤H-500的Fischer大鼠甲状旁腺激素相关肽（PTHRP）产生及高钙血症发展的影响。将睾丸间质细胞瘤皮下植入雄性Fischer大鼠体内，这些大鼠腹腔内持续输注1,25(OH)2D3（50 - 200 pmol/24小时）、EB1089（50 - 400 pmol/24小时）或赋形剂，持续4周。一组未植入肿瘤的对照动物接受类似输注。测定血浆钙、免疫反应性iPTHRP的血浆水平、肿瘤PTHRP mRNA水平以及肿瘤大小、动物体重和动物存活时间。接受>50 pmol/24小时1,25(OH)2D3的未患肿瘤动物出现高钙血症，而接受≤200 pmol/24小时EB1089的动物血浆钙未观察到显著变化。单独接受赋形剂或>50 pmol/24小时1,25(OH)2D3的患肿瘤动物在15天内出现严重高钙血症。然而，用低剂量1,25(OH)2D3和所有剂量EB1089治疗的动物在长达4周的时间内维持血浆钙接近正常或正常水平。此外，与对照组相比，维生素D和EB1089治疗的大鼠肿瘤PTHRP mRNA水平和血浆iPTHRP水平均降低。在实验结束时，输注50 pmol/24小时的1,25(OH)2D3和200 pmol/24小时的EB1089显著减小了肿瘤体积。该类似物而非1,25(OH)2D3显著延长了患肿瘤动物的存活时间，在最高剂量400 pmol/24小时的EB1089下存活时间更长。这些研究表明，1,25(OH)2D3和低血钙维生素D类似物是体内PTHRP产生的有效抑制剂。因此，低血钙类似物可能是恶性肿瘤相关高钙血症的重要替代疗法。
