Document Type

Thesis

Date of Degree

2012

Degree Name

MS (Master of Science)

Degree In

Free Radical and Radiation Biology

First Advisor

Garry R. Buettner

Abstract

High-dose pharmacologic ascorbate has promise as an adjuvant to traditional therapies for cancer. It is hypothesized that the peak plasma concentration is a key determinant in treatment efficacy. From the Phase I clinical trails on the use of pharmacological ascorbate as an adjuvant to Gemcitabine in the treatment of stage IV pancreatic cancer at the University of Iowa Hospitals and Clinics, we found that monitoring plasma ascorbate concentration [AscH-]pl with each infusion is both very time consuming and expensive for large scale implementation. A method to determine the amount and protocol to infuse ascorbate to achieve a desired patient [AscH-]pl would be of great benefit. Current models lack flexibility for various infusion proto- cols. Additionally, constructing a model of ascorbate pharmacokinetics would allow investigation of an optimal dosing regime to maintain constant plasma ascorbate levels.

A mechanistic model and an empirical model were developed and validated. The mechanistic model suitably replicated the results obtained in the clinical trial but contained too many variables to be useful in a clinical setting. The empirical model showed good results in replicating the trial results and requires only a few easily measured variables to generate predictions

High dose ascorbate has been shown to produce hydrogen peroxide. In furthering the studies of how ascorbate affects tumor cells, the action of glucose-6-phosphate dehydrogenase (G6PD) is considered because it supplies NADPH to several peroxide removal pathways. To this end, the kinetics of G6PD were studied using kinetic simulations. G6PD exhibits a reserve capacity, which is the difference between the activity when all intracellular NADP is oxidized to the rate at which is operates when intracellular NADP is at the physiologic 90 % reduced to 10 % oxidized ratio.

These simulations yielded an interesting pattern which is also seen by evolutionary biologists. G6PD exhibits a response capacity, which is the difference between the maximum G6PD activity exhibited when there is no demand for NADPH greater than normal cell functions and the activity exhibited when all cellular NADP is oxidized.

Keywords

Ascorbate, glucose-6-phosphate dehydrogenase, Modeling, NADPH, Pharmacokinetics, response capacity

Pages

xii, 102 pages

Bibliography

Includes bibliographical references (pages 98-102).

Copyright

Copyright 2012 Cameron M. Cushing

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