PROCESSING OF THE NEUROPEPTIDE GROWTH-FACTOR ANTAGONIST [ARG(6), D-TRP(7,9), NMEPHE(8)]-SUBSTANCE-P(6-11) BY A SMALL-CELL LUNG-CANCER CELL-LINE (H69)

被引:4
作者
CUMMINGS, J [1 ]
MACLELLAN, AJ [1 ]
LANGDON, SP [1 ]
JONES, DA [1 ]
ROZENGURT, E [1 ]
SMYTH, JF [1 ]
机构
[1] IMPERIAL CANC RES FUND, LONDON WC2A 3PX, ENGLAND
关键词
METABOLISM; NEUROPEPTIDES; GROWTH FACTORS; ANTAGONISTS; SMALL CELL LUNG CANCER; CELL LINES;
D O I
10.1016/0006-2952(95)00074-A
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
[Arg(6), D-Trp(7,9), NmePhe(8)]-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 mu M, 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 Met(11)) 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.
引用
收藏
页码:1709 / 1712
页数:4
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