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.
BACKGROUND
[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.


METHODS
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.).


RESULTS
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.


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 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.
Cummings
J
J
Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, UK.
MacLellan
A J
AJ
Jones
D A
DA
Langdon
S P
SP
Rozengurt
E
E
Ritchie
A A
AA
Smyth
J F
JF
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009842:Oligopeptides; C095573:arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide