Clive S, Webb D J, MacLellan A, Young A, Byrne B, Robson L, Smyth J F, Jodrell D I
Imperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, UK.
Clin Cancer Res. 2001 Oct;7(10):3071-8.
Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH(2) (Antagonist G), a substance P (SP 6-11) analogue, inhibits mitogenesis stimulated by a broad spectrum of neuropeptides and has demonstrated antitumor activity in vitro and in vivo with IC(50) concentrations of 10-20 microM in small cell lung cancer and other cell lines. Because neuropeptides are part of complex neurohumoral pathways, we have sought to develop novel pharmacodynamic approaches as part of the early clinical development of this potential anticancer drug.
A Phase I trial was performed in two stages. In stage 1, Antagonist G was administered at 3- week intervals using an accelerated dose-escalation strategy until the target maximum plasma concentration (C(max)) of 10 microM was achieved. In stage 2, dose intensity was increased to weekly, and the inhibitory effect of i.v. Antagonist G was assessed by forearm blood flow (FBF) using SP as a vasodilator, as measured by venous plethysmography.
In stage 1, dose was escalated from 2 to 300 mg/m(2) in 12 dose levels using only 15 patients. In stage 2, nine patients were entered at three dose levels (300, 350, and 400 mg/m(2)) and a C(max) of 45 microM was achieved. Facial flushing was the only consistent toxicity but was not dose limiting. FBF studies demonstrated that Antagonist G consistently inhibited the vasodilatory effects of SP (mean, 62 +/- 2% inhibition).
Antagonist G can be safely administered up to 400 mg/m(2), achieving C(max)s >20 microM by weekly 6-h i.v. infusion. FBF studies in patients demonstrated that Antagonist G inhibits SP vasodilatory effects in vivo at these doses in the absence of dose-limiting toxicity.
精氨酸 - D - 色氨酸 - N - 甲基苯丙氨酸 - D - 色氨酸 - 亮氨酸 - 甲硫氨酸 - 酰胺（拮抗剂G）是一种P物质（SP 6 - 11）类似物，可抑制多种神经肽刺激的有丝分裂，并且在体外和体内均显示出抗肿瘤活性，在小细胞肺癌和其他细胞系中的半数抑制浓度（IC50）为10 - 20微摩尔。由于神经肽是复杂神经体液途径的一部分，我们试图开发新的药效学方法，作为这种潜在抗癌药物早期临床开发的一部分。
I期试验分两个阶段进行。在第1阶段，使用加速剂量递增策略，每隔3周给予拮抗剂G，直至达到10微摩尔的目标最大血浆浓度（Cmax）。在第2阶段，给药强度增加到每周一次，通过静脉体积描记法测量前臂血流量（FBF），以SP作为血管扩张剂来评估静脉注射拮抗剂G的抑制作用。
在第1阶段，仅用15名患者，以12个剂量水平将剂量从2毫克/平方米递增至300毫克/平方米。在第2阶段，9名患者进入三个剂量水平（300、350和400毫克/平方米），并达到了45微摩尔的Cmax。面部潮红是唯一持续出现的毒性，但并非剂量限制性毒性。FBF研究表明，拮抗剂G持续抑制SP的血管舒张作用（平均抑制率为62±2%）。
拮抗剂G以高达400毫克/平方米的剂量安全给药，通过每周6小时的静脉输注可使Cmax>20微摩尔。对患者的FBF研究表明，在这些剂量下，拮抗剂G在体内抑制SP的血管舒张作用，且无剂量限制性毒性。
