Disease relevance of Antagonist G

• FBF studies in patients demonstrated that Antagonist G inhibits SP vasodilatory effects in vivo at these doses in the absence of dose-limiting toxicity [1].
• H-Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH2, a broad spectrum neuropeptide growth factor antagonist (antagonist G), is soon to enter a phase I clinical trial for the treatment of small-cell lung cancer (SCLC) [2].

High impact information on Antagonist G

• [Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy [3].
• As well as acting as a neuropeptide receptor antagonist, antagonist G stimulates c-jun-N-terminal kinase (JNK) activity and apoptosis in SCLC cells [3].
• This study shows that antagonist G stimulates apoptosis as assessed by morphology (EC50 = 5.9 +/- 0.1 and 15.2 +/- 2.7 microM for the H69 and H510 cell lines respectively) and stimulates c-jun-N-terminal kinase (JNK) activity in SCLC cells (EC50 = 3.2 +/- 0.1 and 15.2 +/- 2.7 microM) [4].
• In view of these results we show that, as well as acting as a 'broad-spectrum' neuropeptide antagonist, antagonist G stimulates basal G-protein activity in SCLC cell membranes (81 +/- 12% stimulation at 10 microM), thereby displaying a unique ability to stimulate certain signal transduction pathways by activating G-proteins [4].
• 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) [5].

Chemical compound and disease context of Antagonist G

• The ability of a growth factor antagonist, [D-Arg(6),D-Trp(7,9)-N(me)Phe(8)]-substance P(6-11), named antagonist G, to selectively target polyethylene glycol-grafted liposomes (known as sterically stabilized liposomes) to a human classical small cell lung cancer (SCLC) cell line, H69, was examined [6].

Biological context of Antagonist G

• Although antagonist G blocks SCLC cell growth (IC50 = 24.5 +/- 1.5 and 38.5 +/- 1.5 microM for the H69 and H510 cell lines respectively), its exact mechanism of action is unclear [4].
• The major pathway of degradation of antagonist G appeared to be C-terminal methionine oxidation (particularly in plasma) as well as hydrolysis, with even aqueous solutions being significantly affected at low concentrations of peptide (0.1 micrograms ml-1, half life 20.9 h at 37 degrees C) [7].
• 4. Pharmacokinetic studies following systemic (IP) administration to nude mice revealed that the tissue distribution of Antagonist G is likely to be determined by vascular permeability [8].

Anatomical context of Antagonist G

• CONCLUSION: 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 [5].

Associations of Antagonist G with other chemical compounds

• METHODS: The hexapeptide antagonist G was covalently coupled via a thioether bond to the terminus of polyethylene glycol (PEG) in micelles formed from maleimide-derivatized poly(ethylene glycol) (Mr 2000) distearoylphosphatidylethanolamine followed by transfer into preformed liposomes during a one-step incubation [9].

Gene context of Antagonist G

• RESULTS: The postinsertion approach to the formation of peptide-targeted liposomes led to the production of PLG bearing a maximum of approximately 0.3 microg antagonist G/micromol phospholipid [9].
• A sensitive, high efficiency high-performance liquid chromatography (HPLC) method is described for the determination in human plasma of antagonist G and its three major metabolites, deamidated-G (M1), G-minus Met11 (M2) and G[Met11(O)] (M3) [10].
• Our results showed that radiolabeled antagonist G-targeted sterically stabilized liposomes (SLG) bound to H69 cells with higher avidity than free antagonist G and were internalized (reaching a maximum of 13000 SLG/cell), mainly through a receptor-mediated process, likely involving clathrin-coated pits [6].

Analytical, diagnostic and therapeutic context of Antagonist G

• 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 [1].
• [Arg6, D-Trp7.9, NmePhe8]-substance P (6-11) (antagonist G) is a broad spectrum neuropeptide growth factor antagonist about to enter clinical trials as an anticancer drug [11].
• Differential scanning calorimetry studies were conducted to determine the freeze-drying cycle parameters which resulted in a stable, lyophilized formulation of Antagonist G [12].
• Degradation of the basic peptide [Arg6,D-Trp7,9,MePhe8]-substance P (6-11) (antagonist G) was monitored with reversed-phase high-performance liquid chromatography, free capillary zone electrophoresis, and capillary zone electrophoresis with a capillary cationic coating [13].
• Rate constants of the alkaline degradation of antagonist G measured with reversed-phase high-performance liquid chromatography and capillary zone electrophoresis with a dynamic coated capillary wall are similar whereas the values measured with free zone capillary electrophoresis are lower [13].

References