Processing of [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice.
[D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P is a broad-spectrum neuropeptide growth factor antagonist that has exhibited in vitro activity against a range of human cancer cell lines. The fate of this compound in vivo following i.p. administration at 12 micrograms/g to nu/nu mice bearing the H69 small-cell lung cancer xenograft has been studied. Metabolism was confined to the C-terminus producing [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P acid and [D-Arg1,D-Phe5,D-Trp7,9]substance P(1-10). The peptide had a long half-life in plasma (45.9 min) and became widely distributed among the tissues studied with the highest accumulation observed in the liver (AUC 1102 micrograms/g x min) and the lowest in the brain (5 micrograms/g x min). Uptake into the tumor xenograft was poor (AUC 189 micrograms/g x min); however, uptake into the lungs was much greater (AUC 507 micrograms/g x min), offering encouragement that therapeutic concentrations may be targeted to primary lung tumors.
Jones
D A
DA
Imperial Cancer Research Fund, Western General Hospital, Edinburgh, UK.
MacLellan
A J
AJ
Cummings
J
J
Ritchie
A A
AA
Langdon
S P
SP
Smyth
J F
JF
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013373:Substance P / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D013373:Substance P; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-