Induction of FGF as a mechanism of acquired anticancer drug resistance.

摘要

Our laboratory reported that acidic and basic fibroblast growth factors (aFGF/bFGF) confer broad-spectrum chemoresistance in solid tumors. The five studies in this thesis tested the hypothesis that chemotherapy enhances these protein levels, and evaluated the possible role of this enhancement in acquired multidrug resistance (MDR). Results in Chapter 2 show that aFGF and bFGF levels were induced by chemotherapeutic agents with diverse structures and action mechanisms in vitro and in vivo. Studies in Chapter 3 show that bFGF altered the levels of proteins involved in other known drug resistance mechanisms. The data show that bFGF enhanced the levels of GSTπ, Bcl-2, Bcl-x_L, NF-κB/p50, and NF-κB/p65, and that an FGF inhibitor, suramin, reversed bFGF effects. These results suggest bFGF as an upstream event that triggers several known resistance mechanisms. In chapter 4, we evaluated the effect of suramin, at low and non-toxic doses, on the activity of doxorubicin in human prostate tumors. The results show that suramin, at low and nontoxic doses, reversed FGF induced doxorubicin resistance in vitro and improved the effectiveness of doxorubicin in subcutaneous PC3 tumors in immunodeficient mice. These results are consistent with the hypothesis that the FGF-induced resistance can be abolished by suramin. In Chapter 5, we extended our study to non-small cell lung cancer (NSCLC) patients to determine the clinical relevance of drug-induced FGF levels and the prognostic value of plasma bFGF levels. The results show that chemotherapy enhanced the plasma bFGF levels in patients. In addition, there is a significant correlation between changes of pretreatment bFGF levels and patient response. This suggests bFGF level changes are correlated with the clinical outcome. Chapter 6 describes the establishment of an animal model for evaluating the cause-and-effect relationship between drug treatments, induction of intratumoral/plasma bFGF levels, and chemoresistance. The results show that the kinetics of changes in bFGF levels in mice bearing the human colon HT29 xenograft tumors are similar to those in NSCLC patients. Collectively, these results from in vitro, in vivo, and clinical studies show that drug treatment enhanced bFGF levels, and that chemotherapy-induced increases in FGF levels represents a probable mechanism of acquired MDR.