Mechanisms of resistance to fluoropyrimidines

Z G Zhang; A Harstrick; Y M Rustum

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Mechanisms of resistance to fluoropyrimidines

Journal article

Peer reviewed

Mechanisms of resistance to fluoropyrimidines

Z G Zhang, A Harstrick and Y M Rustum

Seminars in oncology, Vol.19(2 Suppl 3), pp.4-9

04/1992

PMID: 1532673

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Abstract

The fluoropyrimidines fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd) have shown activity in a variety of malignancies. Nevertheless, even in initially responsive tumors, the development of resistance is a frequent problem. To understand the biochemical basis for acquired resistance, two pairs of cell lines were investigated. MCF7/Adr cells were obtained from the breast cancer cell line MCF7 by incubation with increasing concentrations of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). These cells are resistant to Adriamycin (200- to 600-fold) and cross-resistant to 5-FU (25-fold) and FdUrd (67-fold). The resistant cells showed significantly increased levels of thymidylate synthase, the target enzyme of the fluoropyrimidines' active metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP). Other biochemical characteristics, including folate pools, drug uptake, metabolism, and retention, were unchanged. Fd9XR cells have been selected from a human colon cancer cell line (HCT-8) by exposure to FdUrd. These cells are resistant to FdUrd (1,000-fold) but not 5-FU. Biochemical evaluations show that the resistant cells are deficient of thymidine kinase and are thus unable to convert FdUrd to FdUMP. This understanding of the various biochemical mechanisms is essential for the design of specific modulations to overcome resistance to fluoropyrimidines.

Cecal Neoplasms - metabolism

Deoxyuracil Nucleotides - metabolism

Drug Resistance

Floxuridine - metabolism

Fluorodeoxyuridylate - metabolism

Fluorouracil - metabolism

Humans

Ileal Neoplasms - metabolism

Leucovorin - pharmacology

Tetrahydrofolates - metabolism

Thymidylate Synthase - antagonists & inhibitors

Thymidylate Synthase - metabolism

Tumor Cells, Cultured

Details

Title: Subtitle: Mechanisms of resistance to fluoropyrimidines
Creators: Z G Zhang - Roswell Park Cancer Institute
A Harstrick
Y M Rustum
Resource Type: Journal article
Publication Details: Seminars in oncology, Vol.19(2 Suppl 3), pp.4-9
PMID: 1532673
ISSN: 0093-7754
eISSN: 1532-8708
Grant note: CA-16056 / NCI NIH HHS CA-21071 / NCI NIH HHS
Language: English
Date published: 04/1992
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359895502771

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