Semester of Graduation

Spring 2018

Degree

Master of Science (MS)

Department

Pathobiological Sciences

Document Type

Dissertation/Thesis

Abstract

Taxanes are spindle poisons that bind to and stabilize microtubules resulting in mitotic arrest. Herpes simplex Typ-1 (HSV-1) virions utilize the microtubular network for intracellular transport during both virus entry and virus egress from infected cells. It has been reported previously that taxanes may synergize with oncolytic herpes simplex viruses in the treatment of experimental prostate and breast tumors in mice. Other reports have indicated that taxanes may inhibit viral replication in infected cells. In this study the previously characterized Oncolytic Herpes Simplex Virus type 1 (OSVP), which was constructed in Kousoulas lab was used in conjugation with paclitaxel (taxol) in 4T1 mouse mammary tumor and RM9 mouse prostate cancer cell lines.

The first goal of this study is to examine the effects of taxol on OSVP life cycle. The effect of taxol on the extent of virus entry, replication and number of infectious virus production were measured. The results showed that virus life cycle is not affected by the presence of taxol in these cell lines despite significant stabilization and reorganization of the microtubular network; visual evidence was also provided by immune fluorescence confocal microscopy reflecting that the virus entry was efficiently followed by intracellular transport and finally infection and spread of the virus to the adjacent cells leading to syncytium formation.

The second goal of this study is to investigate the potency of the constructed OSVP virus in combination with taxol in cancer cell cultures. In various combinations of virus multiplicities of infection and taxol concentrations, enhanced cell killing effects were observed. Moreover, a few of the combination ratios lead to a more pronounced effect characterized as synergistic.

Overall, results confirm that OSVP infection in RM9 and 4T1 cell lines are unaffected by taxol. Moreover, the efficacy and potency of OSVP and taxol are improved when combined. Interestingly, intracellular taxol concentrations and cell cycle analysis results were also affected by virus infection. It is anticipated that taxol-induced leakage of tumors will facilitate spread of OSVP virus within the tumor, producing enhanced tumor destruction and anti-tumor immune responses in addition to the enhanced cellular effect shown in this study.

Date

4-11-2018

Committee Chair

Kousoulas, Gus

Available for download on Tuesday, April 02, 2019

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