| Increased sensitivity of hydroxyurea-resistant leukemic cells to gemcitabine. | |
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MedLine Citation:
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PMID: 10037195 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumor cell resistance to certain chemotherapeutic agents may result in cross-resistance to related antineoplastic agents. To study cross-resistance among inhibitors of ribonucleotide reductase, we developed hydroxyurea-resistant (HU-R) CCRF-CEM cells. These cells were 6-fold more resistant to hydroxyurea than the parent hydroxyurea-sensitive (HU-S) cell line and displayed an increase in the mRNA and protein of the R2 subunit of ribonucleotide reductase. We examined whether HU-R cells were cross-resistant to gemcitabine, a drug that blocks cell proliferation by inhibiting ribonucleotide reductase and incorporating itself into DNA. Contrary to our expectation, HU-R cells had an increased sensitivity to gemcitabine. The IC50 of gemcitabine was 0.061 +/- 0.03 microM for HU-R cells versus 0.16 +/- 0.02 microM for HU-S cells (P = 0.005). The cellular uptake of [3H]gemcitabine and its incorporation into DNA were increased in HU-R cells. Over an 18-h incubation with radiolabeled gemcitabine (0.25 microM), gemcitabine uptake was 286 +/- 37.3 fmol/10(6) cells for HU-R cells and 128 +/- 8.8 fmol/10(6) cells for HU-S cells (P = 0.03). The incorporation of gemcitabine into DNA was 75 +/- 6.7 fmol/10(6) cells for HU-R cells versus 22 +/- 0.6 fmol/10(6) cells for HU-S cells (P < 0.02). Our studies suggest that the increased sensitivity of HU-R cells to gemcitabine results from increased drug uptake by these cells. This, in turn, favors the incorporation of gemcitabine into DNA, resulting in enhanced cytotoxicity. The increased sensitivity of malignant cells to gemcitabine after the development of hydroxyurea resistance may be relevant to the design of chemotherapeutic trials with these drugs. |
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Authors:
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S J Wong; M S Myette; J P Wereley; C R Chitambar |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Clinical cancer research : an official journal of the American Association for Cancer Research Volume: 5 ISSN: 1078-0432 ISO Abbreviation: Clin. Cancer Res. Publication Date: 1999 Feb |
Date Detail:
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Created Date: 1999-04-29 Completed Date: 1999-04-29 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 439-43 Citation Subset: IM |
Affiliation:
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Department of Medicine, Medical College of Wisconsin, Milwaukee 53226, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antimetabolites, Antineoplastic
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metabolism,
pharmacology* Antineoplastic Agents / pharmacology* Cell Division / drug effects DNA, Neoplasm / biosynthesis, drug effects Deoxycytidine / analogs & derivatives*, metabolism, pharmacology Drug Resistance, Neoplasm / genetics Humans Hydroxyurea / pharmacology* Leukemia, Lymphoid / metabolism, pathology Ribonucleotide Reductases / biosynthesis Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA68028/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites, Antineoplastic; 0/Antineoplastic Agents; 0/DNA, Neoplasm; 103882-84-4/gemcitabine; 127-07-1/Hydroxyurea; 951-77-9/Deoxycytidine; EC 1.17.4.-/Ribonucleotide Reductases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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