Award Date

5-1-2012

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Health Physics and Diagnostic Sciences

First Committee Member

Steen Madsen

Second Committee Member

Ralf Sudowe

Third Committee Member

Gary Cerefice

Fourth Committee Member

Janet Dufek

Number of Pages

54

Abstract

Standard treatment protocols for high-grade gliomas, such as glioblastoma multiforme (GBM), are highly ineffective due to their inability to eradicate infiltrating tumor cells. Improvements in overall survival are likely to be realized only with the development of more effective localized therapies capable of eradicating tumor cells in the surgical resection margin and beyond. Photochemical internalization (PCI) is a localized light-based therapeutic modality that enhances the efficacy of therapeutic macromolecules including chemotherapeutic agents such as bleomycin. A number of studies have shown that this photodynamic therapy (PDT) - based modality may prove effective in the treatment of high-grade gliomas.

Three-dimensional multicell human glioma spheroids were used as a tumor model to investigate the efficacy of combination therapies consisting of hyperthermia and PCI. Hyperthermia has been shown to increase the efficacy of a number of therapies including radiation and chemotherapy, however, there have been no studies investigating its utility in combination with PCI.

The results show that hyperthermia and PCI interact in a synergistic manner over a very narrow range of light and temperature levels. In this tumor model, temperatures of 45 °C resulted in total spheroid death: the exact hyperthermic threshold was estimated to be between 42 and 45 °C which provided the rationale for the temperature range investigated (40 - 42 °C). No significant differences in growth kinetics and survival were observed between PCI- and PDT -exposed spheroids at radiant exposures < 1.5 J cm-2. In contrast, all PDT and PCI spheroids irradiated with 3.0 J cm-2 died, suggesting that the useful light range is between 1.5 and 3.0 J cm-2.

A relatively low level of synergism was observed between PCI and hyperthermia at 1.5 J cm-2 and 40 °C, while a high degree of synergism was found when the two modalities were combined at a light level of 2.5 J cm-2 and a temperature of 42 °C. This is the first observation of a synergistic interaction between PCI and hyperthermia and, collectively, the results provide the rationale for additional studies in animal brain tumor models.

Keywords

Bleomycin; Glioblastoma; Glioblastoma multiforme – Treatment; Gliomas – Treatment; Photochemical Internalization; Photochemotherapy; Thermotherapy

Disciplines

Neurology | Neurosciences | Oncology | Physics

Language

English


Share

COinS