imprint:
[Erscheinungsort nicht ermittelbar]: eScholarship, University of California, 2013
Language:
English
Origination:
University thesis:
Dissertation, eScholarship, University of California, 2013
Footnote:
Description:
During the past decades it has been widely assumed that the anticancer drug 5-fluorouracil should be administrated chronically and in low doses to maximize radiosensitization during chemoradiotherapy. However, optimization of the timing and dose administrated of both agents still remains incomplete, as the efficiency of bolus 5FU delivery has never been properly evaluated. In the present dissertation it is shown that the administration of 5FU in high-dose pulses does radiosensitize glioblastoma multiform cells U87MG-VIII and colon cancer cells HCT-116 through modification of alpha and beta ratios in survival fraction curves. Additionally, it was also shown that this radiosensitization last for at least 24 hours if cells are exposed to 2Gy after the 5FU exposure which suggests possible use of 5FU bolus injection together with fractionation schemes. This shift in paradigm from today's protocols could not only help improve fractionated radiotherapy outcomes, but it could greatly benefit patients by shortening clinical stays and lowering overall therapeutic costs. On the other hand, due to the fact that 5FU does not cross the blood brain barrier, other ways to deliver the same to brain tumors were studied. The effect of the administration of the prodrug 5FC, that crosses the blood brain barrier, on the radiosensitization status of glioblastoma multifurme cell lines that contain the gene AC3yCD2, a cytosine deaminase gene (CD), was analyzed. It was shown that the integration of AC3yCD2 on the genome of U87MG-VIII cells does not change the sensitivity of these cells to 5FU, radiation or both agents combined. On the other hand, it was also shown that after the integration of AC3yCD2 on the genome of these cells, the sensitivity of the same to 3 hours exposure of 5FC changed dramatically. Moreover, it was also shown that these changes in sensitivity to 5FC also resulted in a huge radiosensitization effect even at low doses of radiation. These results could be of paramount importance if radiation is incorporated in the protocol of a current clinical trial www.clinicaltrials.gov NCT01156584. Finally, a novel way to target produgs, in particular 5FU, to tumors by taking advantage of the high concentrations of glucose and lactate present in the same is discussed. A molecular switch, MBP317-347, is shown to be a low-affinity switch (being activated at tens of millimolar) for glucose. It is proposed that our low-affinity glucose switch could be used as a proof of concept for a new prodrug therapy strategy denominated Metabolically-directed Enzyme Prodrug Therapy (MDEPT) where glucose or lactate serves as the activators. Additionally, considering the typical differential concentrations of lactate found in tumors and in healthy tissues, our data demonstrates for the first time that a lactate-binding switch analogous to MBP317-347 would be an order of magnitude more active in tumors than in normal tissues and, therefore, would work as a differential activator of anticancer drugs in tumors.