Effects of Taxol on Gene Expression: An Inducible Prostaglandin Endoperoxide Synthase
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Authors
Gorman, Robert R., III
Issue Date
1994
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Taxol is a potent, microtubule-stabilizing, antineoplastic drug that has
demonstrated encouraging efficacy in clinical trials. Unfortunately, many
patients receiving the drug experience significant toxicities, including
hypersensitivity reactions and cardio- and neurotoxicity. Taxol mimics LPS
induction for a number of genes, specifically those encoding proteins which
regulate macrophage activation and tumoricidal activity. Prostaglandin
endoperoxide synthase, known more commonly as cyclooxygenase (COX), is
the rate-limiting enzyme in the biosynthesis of prostaglandins and
thromboxanes from arachidonic acid. The enzyme exists in two isoforms, the
constitutive COX I and the inducible COX II. COX II is induced by
inflammatory mediators such as lipopolysaccharide (LPS) and interleukin-1
(IL-1). This study investigates the possibility that taxol induces COX II gene
expression. Total RNA was isolated from an HL-60 cell line, both from
undifferentiated cells and from cells differentiated to a macrophage-like
phenotype with phorbol ester. COX IT mRNA expression in control cells and
taxol-treated cells was analyzed using the reverse transcriptase-polymerase
chain reaction. For the undifferentiated group, both control and taxol-treated
cells yielded an equivalent COX II signal after 2 hr and 4 hr incubation, but
lost those signals after 12 hr. For the differentiated group, control cells yielded
a signal only after 4 hr incubation. Treated cells yielded a signal after 12 hr
taxol incubation, and this signal was stronger than that for the control group.
These results are consistent with an induction of the COX IT enzyme by taxol.
This provides insight into taxols toxicities and allows for better treatment of
those toxicities, either through the administration of less toxic taxol analogs
or via COX II-specific inhibitors.
Description
ii, 27 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.