Abstract

The efficacy of radiotherapy for cancer is limited by the dose that can be safely delivered to the tumor without causing debilitating side effects. In addition, successful treatment of highly malignant tumors such as glioblastomas is likely to require adjunctive therapies to enhance tumor response to radiation. Previous studies have shown immunomodulation and a synergestic reduction in tumor volume of malignant tumors when tumor necrosis factor-α (TNF-α) protein is administered prior to radiation. The major goal of the present investigation was to evaluate the efficacy of pWS4-human TNF-α (pWS4-hTNF-α), a new plasmid construct that expresses human TNF-α protein, together with radiotherapy in the C6 rat glioma/athymic mouse model in hopes to eradicate invasion of the established tumor. The mice were subcutaneously injected with C6 tumor cells and treatments were begun one day later. Animals received pWS4-hTNF-α complexed with Superfect™ (50 μg DNA + 50 μl Superfect™/injection, 150 μg + 150 μl total in 3 injections) and/or radiation (2 Gy/fraction, 6 Gy total), singly and in combination over an 8-day period; nontreated and other control groups were included. Tumor volumes and body weights were monitored throughout the study. At the time of of leukocyte populations in peripheral blood by flow cytometry, enumeration of leukocytes in blood and spleen, measurements of spontaneous blastogenesis and proliferative capacity in response to mitogenic stimulation, semi-quantitation of leukocyte infiltration into tumors, and determination of human TNF-α in plasma. Tumor presence lead to immune system activation with little or no significant difference among treatment groups. There was an increase in relative spleen weight, total leukocytes/spleen, and leukocyte concentration in peripheral blood. Human TNF-α protein in plasma was below the sensitivity of the assay. Finally, there was a significant increase in mean tumor volume of the tumor control compared to the Superfect™/pWS4-hTNF-α/radiation group. There was a trend towards significantly lower mean tumor volumes among the other experimental groups. These results demonstrate that the Superfect™/pWS4-hTNF-α complex can be safely administered together with radiation under the conditions used and support further investigation to determine an optimal time-dose schedule.

LLU Discipline

Biochemistry

Department

Biochemistry

School

Graduate School

First Advisor

Daila S. Gridley

Second Advisor

Istvan Fodor

Third Advisor

E. Clifford Herrmann

Fourth Advisor

William H.R. Langridge

Degree Name

Master of Science (MS)

Degree Level

M.S.

Year Degree Awarded

1998

Date (Title Page)

6-1998

Language

English

Library of Congress/MESH Subject Headings

Brain Neoplasms; Gene Therapy -- methods; Glioblastoma -- radiotherapy.

Type

Thesis

Page Count

ix; 70

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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