Mechanisms of Resistance and Collateral Sensitivity in Cultured Human MCF-7 Carcinoma Cells Resistant to Pyrazofurin
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Authors
Trautmann, Eric C.
Issue Date
1982
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Pyrazofurin resistant human breast carcinoma (MCF-7)
cells and a subline of clones were developed for studies
aimed at elucidating the mechanisms involved in resistance
to the drug. Enzyme assays indicate that the resistant cells
and clones exhibit increases in the activities
of orotate phosphoribosyl transferase and orotidylate
decarboxylase, pyrazofurin's target enzyme. The appearance
of several resistant clones with no increased enzyme activities
may indicate a deficiency in the levels of adenosine
kinase present. Enzyme kinetic studies suggest that there
is no change in the structure of the target enzyme which
could have caused resistance. The resistant cells show
increased sensitivity to 5-FU. The incorporation of 5-FU
into cellular RNA was compared in resistant and the wild type
cells from which they were derived using radiolabels. The
incorporation was greatly increased in the resistant cells.
The conversion of 5-FU to 5-FUMP was also studied by employing
an enzyme assay and separation via high pressure liquid
chromatography. The conversion is linear with the reaction
time and requires the presence of PRPP. These experiments
indicate that collateral sensitivity to 5-FU is created by
the increased transferase activity in pyrazofurin resistant
cells.
Description
iv, 57 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.