Chemosensitization of pancreatic tumors with the use of low-dose suramin.

摘要

Pancreatic cancer is the fifth leading cause of cancer death in the United States, and ∼30,000 people die from pancreatic cancer each year. Pancreatic tumors are highly chemoresistant (20% response rate) and are most commonly diagnosed at an advanced stage when curative surgery is not possible, resulting in a median survival time of 6 months and a five-year survival rate of 5%. Fibroblast growth factors (FGF) are overexpressed in pancreatic tumors and may play a significant role in the chemoresistance of pancreatic cancer. Our laboratory recently reported that FGFs confer broad-spectrum chemoresistance in solid tumors and that FGF inhibitors enhanced the antitumor activity of several anticancer drugs. Suramin, a nonspecific inhibitor of FGFs, has been shown to enhance the effects of chemotherapy when used at nontoxic, subtherapeutic concentrations.; The effects of low-dose suramin on the activity of GemzarRTM and paclitaxel were evaluated using multiple pharmacodynamic endpoints in mice bearing ectopic and orthotopic Hs 766T pancreatic tumors. Using a suramin dose (10 mg/kg) that enhanced the activity of chemotherapy in lung and prostate tumors, we observed that suramin significantly enhanced the antitumor activity of GemzarRTM and paclitaxel in pancreatic tumors without increasing toxicity. Because FGF expression is higher in pancreatic tumors when compared to lung and prostate tumors, the pharmacodynamics of suramin chemosensitization were also evaluated using increased doses of suramin (30 and 50 mg/kg). All paclitaxel/suramin combinations exhibited similar antitumor effects during treatment. Increased survival benefits were observed when using higher suramin doses, but increasing the suramin dose from 30 to 50 mg/kg provided no additional benefits. The GemzarRTM/paclitaxel combination was also evaluated and was the most effective treatment investigated, but low-dose suramin did not enhance the effects of this combination. Finally, the pharmacokinetics of suramin after oral administration were analyzed. Although plasma concentrations were in the range required for chemosensitization, the bioavailability was 3%. In summary, low-dose suramin significantly enhanced the activity of chemotherapy in pancreatic tumors without increasing toxicity, and results presented in this dissertation support the use of a paclitaxel/suramin combination or a GemzarRTM/paclitaxel combination for the treatment of pancreatic tumors.