Annals of Oncology 6:595-602, 1995
© 1995 European Society for Medical Oncology
research-article |
Pharmacokinetics, metabolism, tissue and tumour distribution of the neuropeptide growth factor antagonist [Arg6, D-Trp7,9, NmePhe8]-substance P (6—11) in nude mice bearing the H69 small-cell lung cancer xenograft*
1Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital Edinburgh
2Imperial Cancer Research Fund London, U.K.
Correspondence to: Jeffrey Cummings, Ph.D. Imperial Cancer Research Fund Medical Oncology Unit Western General Hospital Edinburgh EH4 2XU UK.
BACKGROUND: [Arg6, D-Trp7-9, NmePhe8)-Substance P (6–11) (codenamed antagonist G) represents the first broad 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.
DESIGN: Pharmacokinetics, metabolism, tissue and tumour disposition have been studied in mice (nu/nu) bearing the NCI-H69 human SCLC xenograft after systemic drug administration at an active dose (45 mg/kg i.p.).
RESULTS: The peptide exhibited a 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 (AUC 5278 µg/g x min) and to a lesser extent the spleen (AUC 930 µg/g x min) but only low levels appeared to cross the blood brain barrier (AUC in brain, 20 µg/g x min) or be taken up into the heart (AUC 101 ng/g x min). Tumour uptake was intermediate in value out of the 7 tissues studied (AUC 195 (µg/g x min). Metabolism was restricted almost exclusively to the C terminal of the peptide producing 4 major products: M1, deamidated antagonist G; M2, H-Arg-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 antagonist G; and M4, a combination of H-Arg-DTrp-NmePhe-DTrp-OH and H-DTrp-NmePhe-DTrp-Leu-OH. Extensive bio-transformation to predominately Ml and M2 occurred in most tissues including the tumour where the parent peptide accounted for only 48.5% of the total.
CONCLUSIONS: 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 µM. Taking into account metabolites, a peak concentration of 4.1 µg/g (4.3 uM) 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.
broad spectrum antagonism, neuropeptide growth factors, preclinical pharmacology, small-cell lung cancer
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Clive, D. J. Webb, A. MacLellan, A. Young, B. Byrne, L. Robson, J. F. Smyth, and D. I. Jodrell Forearm Blood Flow and Local Responses to Peptide Vasodilators: A Novel Pharmacodynamic Measure in the Phase I Trial of Antagonist G, a Neuropeptide Growth Factor Antagonist Clin. Cancer Res., October 1, 2001; 7(10): 3071 - 3078. [Abstract] [Full Text] [PDF]
|
|