ABSTRACT
AP25 is an anti-tumor peptide with a high affinity for integrins. It exerts its anti-tumor activity by inhibiting angiogenesis and by directly inhibiting the growth of tumor cells. Its half-life time in vivo is only about 50 minutes, which limits its clinical application. In order to prolong the half-life time of AP25 while preserving its anti-tumor activity, several fusion proteins of AP25 and IgG4 Fc were designed and expressed; their anti-tumor activity and pharmacokinetics properties were evaluated. Firstly, four AP25-Fc fusion protein sequences were designed, and the corresponding proteins were expressed and purified. Based on the results of HUVEC migration inhibition assay, HUVEC and tumor cell proliferation inhibition assay and yields of expression by HEK293 cells, the fusion protein designated PSG4R was selected for further evaluation. The anti-tumor effect of PSG4R was then evaluated in vivo on HCT-116 nude mice xenograft model. And the pharmacokinetics properties of PSG4R were investigated in rats. The results showed that PSG4R could inhibit the growth of xenografts of human colon cancer cell line HCT-116 in nude mice by intravenous administration of 40 mg/kg once every two days. The half-life time of PSG4R was 56.270 ± 15.398 h. This study showed that the construction of AP25-Fc fusion protein could significantly prolong the half-life of AP25 while retaining its anti-tumor activity, which provides a new direction for new drug development of AP25.
Subject(s)
Endostatins/pharmacology , Immunoconjugates/pharmacology , Immunoglobulin G/pharmacology , Neoplasms/drug therapy , Peptide Fragments/pharmacology , Recombinant Fusion Proteins/pharmacology , Administration, Intravenous , Animals , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Endostatins/genetics , Endostatins/therapeutic use , Female , HCT116 Cells , HEK293 Cells , Half-Life , Human Umbilical Vein Endothelial Cells , Humans , Immunoconjugates/genetics , Immunoconjugates/therapeutic use , Immunoglobulin G/genetics , Immunoglobulin G/therapeutic use , Male , Mice , Models, Animal , Neoplasms/pathology , Peptide Fragments/genetics , Peptide Fragments/therapeutic use , Rats , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/therapeutic use , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Aim To evaluate whether the combination of polypeptide AP25 and docetaxel is more efficient in treating experimental breast cancer,than either reagent used alone,and to offer suggestions for clinical use. Methods An experimental breast carcinoma model was set up to investigate the anti-tumor effects of AP25 and docetaxel combination.The Q value was caluculat-ed by Guinness rules and the anti-tumor effects of the combination of polypeptide AP25 and docetaxel were e-valuated.Results The treatment by the combination of polypeptide AP25 and docetaxel showed a better tumor inhibition rate.The combination of AP25 20 mg ·kg -1 and docetaxel 10 mg·kg -1 significantly inhibi-ted the tumor growth with 0.85 1.15,showing a synergistic effect.Conclusions The combination of AP25 and docetaxel can significantly in-hibit the tumor growth with a synergistic effect and de-crease the dose of chemotherapy.
