Background:
bFGF is an important molecule that involved with proliferation, angiogenesis, invasion and metastasis. bFGF expression is closely related with tumor poor prognosis. We have developed new monoclonal antibody targeting bFGF (anti-bFGF mAb) which neutralizes bFGF, blocking its ability to activate FGFR1 in treating solid tumors.
Aim:
The antitumor, antiangiogenesis, antimetastatic and reversal multidrug resistance (MDR) activities of anti-bFGF mAb could be investigated.
Methods:
The effect of anti-bFGF mAb on the proliferation of cancer cells was detected by CCK-8 method. Cellular apoptosis, cell cycle distribution and the expression of associated protein were analyzed by flow cytometry. The expressions of associated protein with apoptosis, metastasis, multidrug resistance, anti-bFGF mAb in suppressing cancer cells growth through the PI3K/AKT/mTOR pathway were examined by real-time fluorescence quantitative PCR and Western blotting. Preclinical pharmacokinetics of anti-bFGF mAb was measured in mice.
Results:
Anti-bFGF mAb significantly could inhibit the proliferation and induce apoptosis of melanoma, lung cancer and breast cancer cells, and show obvous inhibitory effects on the migration of cancer cells and the tube formation of HUVECs in vitro. Treatment of transplanted cancer with anti-bFGF mAb in vivo resulted in significant reduction in tumor size and prolonged survival time of mice. The expression of caspase-3，caspase-9, PARP, and BAX in combination group was higher than those from either agent alone. Anti-bFGF mAb suppressed the PI3K/AKT/mTOR pathway. The radiotherapy sensitization enhancement ratio of the combined treatment group increased 2.37 times by anti-bFGF mAb. bFGF, VEGF expression and MVD were significantly decreased by anti-bFGF mAb. Anti-bFGF mAb could induce down-regulated P-glycoprotein and MDR1 . The main pharmacokinetic parameters of anti-bFGF mab were as follows: T1/2α 0.2 h，T1/2β 1.84h and T1/2γ 90.3h. lung tissue was major organ for deposition of anti-bFGFmAb.
Conclusions:
Our data indicate that anti-bFGF mAbs display remarkable and potential therapeutic candidates for melanoma, lung cancer and breast.