Previous studies in our laboratory showed that low-dose suramin, an inhibitor of fibroblast growth factor action, enhances sensitivity of various human tumors in preclinical and clinical studies to chemotherapy. Chemosensitization required apoptosis, and increased the extent and duration of the induction of apoptosis. The primary focus of this dissertation research was to explore, in preclinical studies, therapeutic approaches for therapy enhancement based on this mechanism.
A phase III clinical trial in superficial bladder cancer, which emanated from our laboratory, showed that optimizing mitomycin C delivery nearly doubled the recurrence-free survival of treated patients to 40%. Tumor sensitization with suramin might yield further therapeutic improvements, and was investigated in in vitro and in vivo studies. Studies in Chapter 2 demonstrated enhanced antitumor activity of mitomycin C, administered at subtherapeutic and therapeutic regimens.
Various preclinical and clinical studies determined that suramin sensitized tumor tissue at low but not at high concentrations, presumably due to additional pharmacologic effects at elevated concentrations. Studies to overcome this limitation, especially in tumors containing high fibroblast growth factor concentrations, used pentosan polysulfate, another nonspecific FGF inhibitor. This agent was also a chemosensitizer, but combined use with suramin did not increase the overall efficacy (Chapter 3).
Radiotherapy depends on induction of apoptosis for its anticancer effect, as is the case for many forms of chemotherapy, and led to our evaluation of suramin as radiosensitizer. Results in Chapter 4 and Chapter 5 showed that low-dose suramin sensitized the radiation response of both radiosensitive (prostate PC-3) and relatively radioresistant (pharynx FaDu, pancreatic Hs 766T) xenograft tumors, thereby further extending the clinical application of suramin to modulate radiotherapy. More importantly, the radiosensitizaiton effect of suramin had tumor type specific dose dependence, with a narrow sensitiziting window in FaDu and a wider range in Hs 766T (pancreatic) xenograft tumors (Chapter 5), suggesting the necessity of drug target-specified dosing regimen for suramin. To better understand the biphasic effect of suramin in combination with radiation, pharamacodynamic studies at a microscopic level were conducted (Chapter 6). The results indicated that low-dose but not high-dose suramin enhanced radiation-induced apoptosis, inhibiting radiation-induced upregulation of phospho-ERK and survivin, two survival signals involved in radioresistance.
|Advisor:||Wientjes, M. Guillaume|
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/09(E), Dissertation Abstracts International|
|Keywords:||Chemosensitizer, Mitomycin C, Paclitaxel, Radiosensitizer, Suramin, Survivin|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be