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.
OBJECTIVE
Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH(2) (Antagonist G), a substance P (SP 6-11) analogue, inhibits mitogenesis stimulated by a broad spectrum of neuropeptides and has demonstrated antitumor activity in vitro and in vivo with IC(50) concentrations of 10-20 microM in small cell lung cancer and other cell lines. Because neuropeptides are part of complex neurohumoral pathways, we have sought to develop novel pharmacodynamic approaches as part of the early clinical development of this potential anticancer drug.


METHODS
A Phase I trial was performed in two stages. In stage 1, Antagonist G was administered at 3- week intervals using an accelerated dose-escalation strategy until the target maximum plasma concentration (C(max)) of 10 microM was achieved. In stage 2, dose intensity was increased to weekly, and the inhibitory effect of i.v. Antagonist G was assessed by forearm blood flow (FBF) using SP as a vasodilator, as measured by venous plethysmography.


RESULTS
In stage 1, dose was escalated from 2 to 300 mg/m(2) in 12 dose levels using only 15 patients. In stage 2, nine patients were entered at three dose levels (300, 350, and 400 mg/m(2)) and a C(max) of 45 microM was achieved. Facial flushing was the only consistent toxicity but was not dose limiting. FBF studies demonstrated that Antagonist G consistently inhibited the vasodilatory effects of SP (mean, 62 +/- 2% inhibition).


CONCLUSIONS
Antagonist G can be safely administered up to 400 mg/m(2), achieving C(max)s >20 microM by weekly 6-h i.v. infusion. FBF studies in patients demonstrated that Antagonist G inhibits SP vasodilatory effects in vivo at these doses in the absence of dose-limiting toxicity.
Clive
S
S
Imperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, Scotland, UK.
Webb
D J
DJ
MacLellan
A
A
Young
A
A
Byrne
B
B
Robson
L
L
Smyth
J F
JF
Jodrell
D I
DI
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001916:Brachial Artery / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005483:Flushing / Q000139:chemically induced; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007260:Infusion Pumps; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D009479:Neuropeptides / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012039:Regional Blood Flow / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009479:Neuropeptides; D009842:Oligopeptides; D014665:Vasodilator Agents; C095573:arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide; D013373:Substance P; D001920:Bradykinin