| Basic fibroblast growth factor as a therapeutic target for chemosensitization in colorectal cancer | |||||||||||||||
Abstract | |||||||||||||||
| Recently, our lab reported an epigenetic mechanism of multidrug resistance that is mediated by acidic and basic fibroblast growth factors (aFGF and bFGF) expressed in solid tumors. Suramin, a non-specific FGF inhibitor, enhanced the antitumor activity of several anticancer drugs in vivo condition in prostrate, bladder, pancreatic, lung and breast cancer. Based on these initial findings, the studies proposed in this dissertation are focused on improving the understanding of FGF-targeted therapy for chemotherapy in an in vivo system in colorectal cancer (CRC). Studies in Chapter 2 showed specific inhibitor of bFGF but not aFGF significantly enhanced antitumor activity of CPT-11. This indicated bFGF is a potential therapeutic target for chemotherapy in CRC. Meanwhile, studies in Chapter 3 showed CPT-11 enhanced intratumoral bFGF level during chemotherapy, and also upregulated bFGF level in recurrent tumors after chemotherapy. Together with the earlier observations, this suggested chemotherapy-induced bFGF level might be a potential mechanism of acquired drug resistance in CRC. Antitumor effect of suramin, an available and relative smaller bFGF inhibitor compared to anti body, was evaluated in Chapter 4. Results showed low-dose suramin enhanced antitumor effect of CPT-11. Chapter 5 further clarified effect of suramin in chemotherapy was associated with bFGF inhibition in vivo condition in CRC. This supported using suramin as a non-specific bFGF inhibitor and chemosensitizer in treating CRC. To evaluate what suramin dose gives optimal enhancement to CPT-11, studies in Chapter 6 showed higher dose of low-dose suramin exhibited best chemosensitization effects. We also found high-dose suramin exhibited delayed tumor regrowth compared to low-dose suramin, which provided a hypothesis for future study on suramin. Collectively, these studies indicated that bFGF is a therapeutic target for chemosensitization in colorectal cancer, also low-dose suramin as a non-specific bFGF inhibitor sensitized CPT-11, which strongly support using low-dose suramin in treating CRC. | |||||||||||||||
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