TY - JOUR
T1 - HT1080/DR4
T2 - A P-glycoprotein-negative human fibrosarcoma cell line exhibiting resistance to topoisomerase II-reactive drugs despite the presence of a drug-sensitive topoisomerase ii
AU - Zwelling, Leonard A.
AU - Slovak, Marilyn L.
AU - Doroshow, James H.
AU - Hinds, Michael
AU - Chan, Diana
AU - Parker, Elizabeth
AU - Mayes, Janice
AU - Sie, Kiem Lan
AU - Meltzer, Paul S.
AU - Trent, Jeffrey M.
N1 - Funding Information:
Received June 4, 1990; accepted July 17, 1990. Supported by Public Health Service research grants CA-40090, CA-41183, CA-31788, and CA-39809 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by grant CH-324B from the American Cancer Society; by a grant from the Dunn Foundation; and by a gift to the M. D. Anderson Annual Fund for the Chemotherapy Research Program from Mr. Henry C. Beck, Jr., of Dallas, Tex. L. A. Zwelling, M. Hinds, D. Chan, J. Mayes, K. L. Sie (Department of Medical Oncology), E. Parker (Department of Hematology), The University of Texas M. D. Anderson Cancer Center, Houston, Tex. M. L. Slovak (Department of Cytogenetics), J. H. Doroshow (Department of Medical Oncology and Therapeutics Research), City of Hope National Medical Center, Duarte, Calif. P. S. Meltzer, J. M. Trent, The Arizona Cancer Center, Tucson, Ariz. We thank Dr. Leroy Liu of The Johns Hopkins School of Medicine for his gift of the antihuman topoisomerase II antibody, Dr. Bonnie Glisson of The University of Texas M. D. Anderson Cancer Center for critical reading of the manuscript, and Diane Rivera for editing the paper. Correspondence to: Leonard A. Zwelling, M.D., Department of Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 52, Houston, TX 77030.
PY - 1990/10/3
Y1 - 1990/10/3
N2 - HT1080/DR4 (DR4) is a doxorubicin-resistant human fibrosarcma line that exhibits 150-fold cross-resistance to etoposide but does not overexpress P-glycoprotein (one mechanism of multiple drug resistance). We examined anothe possible of multiple drug resistance). We examined another possible mechanism that could explain resistance to bothe doxorubicin and etoposide: a quantitative or qualitative alteration in topoisomerase II, the putative nuclear target of these agents. The amount of immunoreactive topoisomerase II present in whole-cell Iysates and nuclear extracts was three- to 10-fold lower in DRA than in HT1080 cells. However the topoisomerase II in nuclear extracts from both lines was sensitive to the effects of amascrine (AMSA) and etoposide. Following treatment with AMSA, etoposide, and 5-iminodaunorubicin, topoisomerase II-mediated DNA cleavage in DRA cells and nuclei was reduced compared with cleavage in HT1080 parent cells and nuclei. The difference between the Ht1080 and DR4 lines in AMSA-and 5-iminodaunorubicin-induced cleavage was similar in cells and nuclei and could be due to the lower amount of DR4 topoisomerase II. By contrast, the difference between the HT1080 and DR4 lines in etoposideinduced DNA cleavage was much greater in cells than in nuclei. This finding suggested that cytosolic factors, removed from isolated nuclei, could influence the susceptibility of intact cells to the cyotoxic and DNA-cleaving actions of etoposide. The specific activities of several against free-radical damage that may be produced by doxorubicin or etoposide, were significantly differences may constitute an additional mechanism of resistance. Regardless, the magnitude of the resistance of DR4 to doxorubicin and etoposide cannot be explained solely on the basis of a topoisomerase II-related mechanism.[J Natl Cancer Inst 82:1553-1561, 1990].
AB - HT1080/DR4 (DR4) is a doxorubicin-resistant human fibrosarcma line that exhibits 150-fold cross-resistance to etoposide but does not overexpress P-glycoprotein (one mechanism of multiple drug resistance). We examined anothe possible of multiple drug resistance). We examined another possible mechanism that could explain resistance to bothe doxorubicin and etoposide: a quantitative or qualitative alteration in topoisomerase II, the putative nuclear target of these agents. The amount of immunoreactive topoisomerase II present in whole-cell Iysates and nuclear extracts was three- to 10-fold lower in DRA than in HT1080 cells. However the topoisomerase II in nuclear extracts from both lines was sensitive to the effects of amascrine (AMSA) and etoposide. Following treatment with AMSA, etoposide, and 5-iminodaunorubicin, topoisomerase II-mediated DNA cleavage in DRA cells and nuclei was reduced compared with cleavage in HT1080 parent cells and nuclei. The difference between the Ht1080 and DR4 lines in AMSA-and 5-iminodaunorubicin-induced cleavage was similar in cells and nuclei and could be due to the lower amount of DR4 topoisomerase II. By contrast, the difference between the HT1080 and DR4 lines in etoposideinduced DNA cleavage was much greater in cells than in nuclei. This finding suggested that cytosolic factors, removed from isolated nuclei, could influence the susceptibility of intact cells to the cyotoxic and DNA-cleaving actions of etoposide. The specific activities of several against free-radical damage that may be produced by doxorubicin or etoposide, were significantly differences may constitute an additional mechanism of resistance. Regardless, the magnitude of the resistance of DR4 to doxorubicin and etoposide cannot be explained solely on the basis of a topoisomerase II-related mechanism.[J Natl Cancer Inst 82:1553-1561, 1990].
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U2 - 10.1093/jnci/82.19.1553
DO - 10.1093/jnci/82.19.1553
M3 - Article
C2 - 1976136
AN - SCOPUS:0025118359
SN - 0027-8874
VL - 82
SP - 1553
EP - 1561
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 19
ER -