Antitumor activities of dFv-LDP-AE: An enediyne-energized fusion protein             targeting tumor-associated antigen gelatinases.
Gelatinases play an important role in tumor growth and metastasis, and overexpression             of these molecules is strongly correlated with poor prognosis in a variety of             malignant tumors. Lidamycin is an enediyne antitumor antibiotic with potent cytotoxicity.             We previously reported that a tandem scFv format (dFv-LDP-AE) showed enhanced             binding ability with gelatinases compared with the scFv-lidamycin conjugate (Fv-LDP-AE).             In this study, the antitumor activities of dFv-LDP-AE on hepatocellular carcinoma             (HCC) were evaluated in vitro and in vivo. By SDS-PAGE analysis, it was found             that partial fusion protein dFv-LDP existed as dimer; the results of ELISA and             immunofluorescence demonstrated that the fusion protein dFv-LDP could efficiently             bind to hepatoma cells in vitro. The apparent arrest of cell cycle at G2/M phase             and induction of apoptosis at nanomole levels indicated that the dFv-LDP-AE was             very potent against HCC. In in vivo experiments, dFv-LDP-AE shown enhanced cytotoxic             effects compared to those of LDM. Administration at mouse tolerable dosage level,             the inhibition rate of tumor growth was 89.5% of dFv-LDP-AE vs. 73.6% of LDM on             transplantable H22 in mice (P<0.05) and, 87.3% of dFv-LDP-AE vs. 63.4% of LDM             on hepatoma Bel-7402 in athymic mice (P<0.01). Small animal optical imaging             showed that the FITC-labeled dFv-LDP preferentially localized in the tumor site             in less than 30 min, which demonstrated remarkable tumor-targeting properties.             Taken together with the above findings, the enediyne-energized fusion protein             dFv-LDP-AE showed potential application as a new agent for therapeutic appications             in HCC.
The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province 453100, PR China.
Gen-Shen
GS
Zhong
Min-Na
MN
Wu
Xiao-Fang
XF
Guo
Sheng-Hua
SH
Zhang
Qing-Fang
QF
Miao
Yong-Su
YS
Zhen
D000617:Aminoglycosides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D053281:Enediynes / Q000378:metabolism / Q000494:pharmacology*; D018093:Gelatinases / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000276:immunology / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C058024:C 1027; D018093:Gelatinases