Molecular Pharmacodynamics of Chemotherapy: Fibroblast Growth Factor (FGF) Inhibitors as Chemosensitizers

摘要

Au and Wientjes et al. recently reported that acidic (aFGF) and basic (bFGF) fibroblast growth factors confer a broad spectrum chemoresistance in solid tumors, and that suramin, a non-specific FGF inhibitor, enhanced the in vitro anti-tumor activity of several anticancer drugs. Based on this initial finding, the studies proposed in this dissertation are focused on improving the understanding of the mechanisms of the FGF-induced resistance and the molecular pharmacodynamics of suramin. Studies in Chapter 2 show suramin can enhance the therapeutic efficacy of chemotherapy in lung cancer, thus establishing the in vivo efficacy of low dose suramin. Studies in Chapter 3 show bFGF is a clinically significant predictor of chemotherapy and suramin effect. Many literature reports show suramin as having anti-angiogenic properties, therefore the possibly of an anti-angiogenic mechanism for suramin was investigated in both in vitro (Chapter 4) and in vivo (Chapter 5) models. Results from Chapter 4 show low doses of suramin alone had no effect compared to control and suramin in combination with chemotherapy had no additional effects as compared to chemotherapy alone in a monolayer endothelial cell model. This finding was extended to an in vitro tumor histoculture model and the results show the suramin effects were vasculature independent. Results from Chapter 5 show that suramin alone had no effect on the in vivo tumor vessel morphology, and suramin did not show any additional effects when combined with chemotherapy. The functionality of the tumor vessels was also tested and the results show that chemotherapy greatly increased the functionality of the tumor vasculature; however there were no additional effects from suramin. Collectively, these studies show suramin is capable of sensitizing tumors to chemotherapy, bFGF is a valid biomarker for chemotherapy and suramin sensitization effect, and that the in vivo mechanism of suramin chemosensitization is not due to anti-angiogenesis.