Cummings J, MacLellan A J, Langdon S P, Jones D A, Rozengurt E, Smyth J F
Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
Biochem Pharmacol. 1995 May 26;49(11):1709-12. doi: 10.1016/0006-2952(95)00074-a.
[Arg6, D-Trp7.9, NmePhe8]-substance P (6-11) (antagonist G) is a broad spectrum neuropeptide growth factor antagonist about to enter clinical trials as an anticancer drug. Its fate has been studied after incubation with two densities (5 x 10(4) cells/mL and 1 x 10(6) cells/mL) of the H69 small cell lung cancer cell line for up to 7 days at a concentration of 20 microM, corresponding to the IC50 for growth inhibition. HPLC analyses were conducted on cell pellets and media and in controls consisting of cell free media and water. Over 7 days in media containing cells a 70.4% reduction in parent peptide concentration occurred at the high density and a 44.1% reduction at low density. Despite this, there was a steady elevation in peptide associated with cells reaching a 189% increase by day 7. Oxidation of G at the C-terminal methionine residue occurred in all media studied indicative of a chemical process. The two major active metabolites of antagonist G (deamidated G and G minus Met11) were detected only in media in the presence of cells. These accumulated with time in media and cells together with oxidized products. These results reveal complex cellular pharmacology for antagonist G where H69 cells are increasingly exposed to 4 different peptide products rather than 1.
[精氨酸6、D-色氨酸7.9、N-甲基苯丙氨酸8] -P物质（6-11）（拮抗剂G）是一种广谱神经肽生长因子拮抗剂，即将作为抗癌药物进入临床试验。在与两种密度（5×10⁴细胞/毫升和1×10⁶细胞/毫升）的H69小细胞肺癌细胞系在20微摩尔浓度下孵育长达7天（该浓度对应生长抑制的IC50）后，对其命运进行了研究。对细胞沉淀和培养基以及由无细胞培养基和水组成的对照进行了HPLC分析。在含有细胞的培养基中培养7天期间，高密度时母体肽浓度降低了70.4%，低密度时降低了44.1%。尽管如此，与细胞相关的肽稳步升高，到第7天增加了189%。在所研究的所有培养基中，G的C末端甲硫氨酸残基均发生氧化，这表明存在化学过程。拮抗剂G的两种主要活性代谢物（脱酰胺G和G减去甲硫氨酸11）仅在有细胞存在的培养基中检测到。它们在培养基和细胞中随时间积累，并伴有氧化产物。这些结果揭示了拮抗剂G复杂的细胞药理学，其中H69细胞越来越多地接触到4种不同的肽产物而非1种。
