Cummings J, MacLellan A J, Jones D A, Langdon S P, Rozengurt E, Ritchie A A, Smyth J F
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
Ann Oncol. 1995 Jul;6(6):595-602. doi: 10.1093/oxfordjournals.annonc.a059250.
[Arg6, D-Trp7,9, NmePhe8]-Substance P (6-11) (codenamed antagonist G) represents the first board spectrum antagonist of a number of neuropeptides shown to act as growth factors in small-cell lung cancer (SCLC) and is shortly to enter clinical trials.
Pharmacokinetics, metabolism, tissue disposition have been studied in mice (nu/nu) bearing the NCI-H69 human SCLC xenograft after systemic drug adminstration at an active dose (45 mg/kg i.p.).
The peptide exhibited relatively long half life (28.9 min; clearance 45.6 ml/min/kg) and distributed widely (volume of distribution 1490 ml/kg). Marked accumulation of antagonist G (and its metabolites) was noted in the liver (AUC5278 micrograms/g x min) and to a lesser extent the spleen (AUC 930 micrograms/g x min) but only low levels appeared to cross the blood brain barrier (AUC in brain, 20 micrograms/g x min) or be taken up into the heart (AUC 101 micrograms/g x min). Tumour uptake was intermediate in value out of the 7 tissues studied (AUC 195 micrograms/g x min). Metabolism was restricted almost exclusively to the C terminal of the peptide producing 4 major products: M1, deamidated antagonist G; M2, Harg-DTrp-NmePhe-DTrp-Leu-OH, both of which retain growth factor antagonist activity; M3, a combination of oxidised antagonist G [Met11(O)] and oxidised deamidated antagoinst G; and M4, a combination of H-Arg-DTrp-NmePhe-DTrp-OH and H-DTrp-NmePhe-DTrp-Leu-OH. Extensive biotransformation to predominately M1 and M2 occurred in most tissues including the tumour where the parent peptide accounted for only 48.5% of the total.
Levels of antagonist G required to produce a small but significant effect on the growth of SCLC cell lines in vitro are in the region of 4-7 microM. Taking into account metabolites, a peak concentration of 4.1 microgram/g (4.3 microM) was achieved in the H69 xenograft. These studies reveal a favourable preclinical pharmacology profile for antagonist G and offer hope that anticancer activity may be achievable in man.
[精氨酸6、D-色氨酸7,9、N-甲基苯丙氨酸8]-P物质（6-11）（代号为拮抗剂G）是多种神经肽的首个广谱拮抗剂，这些神经肽在小细胞肺癌（SCLC）中可作为生长因子起作用，且即将进入临床试验。
在以活性剂量（45mg/kg腹腔注射）全身给药后，对携带NCI-H69人SCLC异种移植瘤的裸鼠（nu/nu）进行了药代动力学、代谢及组织分布研究。
该肽表现出相对较长的半衰期（28.9分钟；清除率45.6ml/分钟/kg），分布广泛（分布容积1490ml/kg）。在肝脏中观察到拮抗剂G（及其代谢产物）有明显蓄积（AUC为5278微克/克×分钟），在脾脏中的蓄积程度较小（AUC为930微克/克×分钟），但似乎只有低水平的药物穿过血脑屏障（脑内AUC为20微克/克×分钟）或被心脏摄取（AUC为101微克/克×分钟）。在所研究的7个组织中，肿瘤摄取量处于中等水平（AUC为195微克/克×分钟）。代谢几乎完全局限于肽的C末端，产生4种主要产物：M1，脱酰胺化拮抗剂G；M2，Harg-DTrp-NmePhe-DTrp-Leu-OH，两者均保留生长因子拮抗剂活性；M3，氧化拮抗剂G[Met11（O）]和氧化脱酰胺化拮抗剂G的组合；以及M4，H-Arg-DTrp-NmePhe-DTrp-OH和H-DTrp-NmePhe-DTrp-Leu-OH的组合。在包括肿瘤在内的大多数组织中，广泛发生生物转化，主要生成M1和M2，在肿瘤中，母体肽仅占总量的48.5%。
在体外对SCLC细胞系生长产生微小但显著影响所需的拮抗剂G水平在4-7微摩尔范围内。考虑到代谢产物，在H69异种移植瘤中达到的峰值浓度为4.1微克/克（4.3微摩尔）。这些研究揭示了拮抗剂G良好的临床前药理学特征，并带来了在人体中实现抗癌活性的希望。
