Miller V A, Rigas J R, Benedetti F M, Verret A L, Tong W P, Kris M G, Gill G M, Loewen G R, Truglia J A, Ulm E H, Warrell R P
Thoracic Oncology, Developmental Chemotherapy, and Leukemia Services, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Clin Cancer Res. 1996 Mar;2(3):471-5.
The retinoid response is mediated by families of nuclear receptors, the retinoic acid receptors (RARs), and the retinoid X receptors. All-trans retinoic acid (RA) binds only RARs and induces its own metabolism. In contrast, 9-cis RA is a newly identified agonist for both RARs and retinoid X receptors. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of 9-cis RA in patients with advanced cancer. Thirty-four patients received once daily p.o. doses of 9-cis RA (administered as LGD1057) ranging from 5 to 230 mg/m2 for 4 weeks. Pharmacokinetic studies were performed on 28 patients at seven dose levels. 9-cis RA was generally well tolerated. Headache was the most common dose-limiting adverse effect. Other prominent reactions included facial flushing, myalgia, dyspnea, hypertriglyceridemia, and hypercalcemia. Relative to other retinoids, mucocutaneous reactions were mild. No major antitumor responses were observed. Pharmacokinetic analysis revealed that the day 1 area under the plasma concentration x time curves (AUCs) were proportional to the dose. Up through doses of 140 mg/m2, the day 1 AUCs were similar to those on days 15 and 29. At higher doses, however, AUCs tended to decline with repeat dosing. 9-cis RA is a novel compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor cell proliferation and differentiation. We recommend a dose of 140 mg/m2 for single-agent trials utilizing a once-daily schedule of administration.
类视黄醇反应由核受体家族介导，即维甲酸受体（RARs）和类视黄醇X受体。全反式维甲酸（RA）仅与RARs结合并诱导自身代谢。相比之下，9-顺式RA是一种新发现的RARs和类视黄醇X受体激动剂。我们进行了一项剂量范围研究，以检查9-顺式RA在晚期癌症患者中的安全性、临床耐受性和药代动力学。34例患者口服9-顺式RA（以LGD1057形式给药），剂量范围为5至230mg/m²，每日一次，共4周。在7个剂量水平上对28例患者进行了药代动力学研究。9-顺式RA总体耐受性良好。头痛是最常见的剂量限制性不良反应。其他突出反应包括面部潮红、肌痛、呼吸困难、高甘油三酯血症和高钙血症。相对于其他类视黄醇，皮肤黏膜反应较轻。未观察到主要的抗肿瘤反应。药代动力学分析显示，第1天血浆浓度-时间曲线下面积（AUCs）与剂量成正比。直至140mg/m²剂量，第1天的AUCs与第15天和第29天相似。然而，在更高剂量下，重复给药时AUCs往往会下降。9-顺式RA是一种新型化合物，它利用了一条新发现的类视黄醇受体生物学途径，这可能与肿瘤细胞增殖和分化有关。我们建议在单药试验中采用每日一次给药方案时，剂量为140mg/m²。
