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Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells.
Blood. 1997 Mar 15; 89(6):2098-104.Blood

Abstract

Topotecan (TPT) is a topoisomerase I (topo I) poison that has shown promising antineoplastic activity in solid tumors and acute leukemia. In the present study, a band depletion assay was used to evaluate the ability of TPT to stabilize topo I-DNA adducts in human leukemia cell lines and in clinical leukemia samples ex vivo. This assay showed that 50% of the cellular topo I in HL-60 human myelomonocytic leukemia cells became covalently bound to DNA at an extracellular TPT concentration of 4 micromol/L. In contrast, in 13 clinical specimens of human leukemia harvested before treatment of patients with TPT, the TPT concentration required to stabilize 50% of the cellular topo I in topo I-DNA complexes ranged from 3 to greater than 100 micromol/L (median, 30 micromol/ L). Flow microfluorimetry showed that cellular TPT accumulation varied over only a twofold range and failed to provide evidence for transport-mediated resistance in the clinical samples. These observations raise the possibility that formation of topo I-DNA adducts is diminished in many specimens of refractory/relapsed acute leukemia by a mechanism that might alter topo I sensitivity to TPT.

Authors+Show Affiliations

Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9058732

Citation

Kaufmann, S H., et al. "Altered Formation of Topotecan-stabilized Topoisomerase I-DNA Adducts in Human Leukemia Cells." Blood, vol. 89, no. 6, 1997, pp. 2098-104.
Kaufmann SH, Svingen PA, Gore SD, et al. Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. Blood. 1997;89(6):2098-104.
Kaufmann, S. H., Svingen, P. A., Gore, S. D., Armstrong, D. K., Cheng, Y. C., & Rowinsky, E. K. (1997). Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. Blood, 89(6), 2098-104.
Kaufmann SH, et al. Altered Formation of Topotecan-stabilized Topoisomerase I-DNA Adducts in Human Leukemia Cells. Blood. 1997 Mar 15;89(6):2098-104. PubMed PMID: 9058732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells. AU - Kaufmann,S H, AU - Svingen,P A, AU - Gore,S D, AU - Armstrong,D K, AU - Cheng,Y C, AU - Rowinsky,E K, PY - 1997/3/15/pubmed PY - 1997/3/15/medline PY - 1997/3/15/entrez SP - 2098 EP - 104 JF - Blood JO - Blood VL - 89 IS - 6 N2 - Topotecan (TPT) is a topoisomerase I (topo I) poison that has shown promising antineoplastic activity in solid tumors and acute leukemia. In the present study, a band depletion assay was used to evaluate the ability of TPT to stabilize topo I-DNA adducts in human leukemia cell lines and in clinical leukemia samples ex vivo. This assay showed that 50% of the cellular topo I in HL-60 human myelomonocytic leukemia cells became covalently bound to DNA at an extracellular TPT concentration of 4 micromol/L. In contrast, in 13 clinical specimens of human leukemia harvested before treatment of patients with TPT, the TPT concentration required to stabilize 50% of the cellular topo I in topo I-DNA complexes ranged from 3 to greater than 100 micromol/L (median, 30 micromol/ L). Flow microfluorimetry showed that cellular TPT accumulation varied over only a twofold range and failed to provide evidence for transport-mediated resistance in the clinical samples. These observations raise the possibility that formation of topo I-DNA adducts is diminished in many specimens of refractory/relapsed acute leukemia by a mechanism that might alter topo I sensitivity to TPT. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/9058732/Altered_formation_of_topotecan_stabilized_topoisomerase_I_DNA_adducts_in_human_leukemia_cells_ DB - PRIME DP - Unbound Medicine ER -