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Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site.
Cancer Res. 2001 Jan 15; 61(2):504-8.CR

Abstract

NB-506 is a topoisomerase I (top1) inhibitor in clinical trials. In this study, we used a series of camptothecin (CPT)-resistant cell lines with known top1 alterations. We show that three mutations in different domains of the top1 enzyme that confer CPT resistance also confer cross-resistance to NB-506. The CPT-resistant cell lines and corresponding mutations were: human prostate carcinoma cells DU-145/RC1 (mutation R364H), Chinese hamster fibroblasts DC3F/C10 (mutation G503S), and human leukemia CEM/C2 cells (N722S). This result suggests that NB-506 and CPT share a common binding site in the top1-DNA complex. We next used these three cell lines and their parental cells to study the relationship between top1 poisoning by NB-506 and antiproliferative activity. We found that the CPT-resistant cells were only 2-10-fold resistant to NB-506, which suggests that NB-506 targets other cellular processes/pathways besides top1. This conclusion was further supported by the limited cross-resistance of top1-deficient murine leukemia P388/CPT45 cells (2-fold). Cross-resistance was also limited for J-109,382, an isomer of NB-506 that does not intercalate into DNA, indicating that the non-top1-mediated antiproliferative activity of NB-506 is not attributable to DNA intercalation. Together, these data indicate that NB-506 and indolocarbazoles are promising agents to overcome CPT resistance.

Authors+Show Affiliations

Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11212241

Citation

Urasaki, Y, et al. "Use of Camptothecin-resistant Mammalian Cell Lines to Evaluate the Role of Topoisomerase I in the Antiproliferative Activity of the Indolocarbazole, NB-506, and Its Topoisomerase I Binding Site." Cancer Research, vol. 61, no. 2, 2001, pp. 504-8.
Urasaki Y, Laco G, Takebayashi Y, et al. Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site. Cancer Res. 2001;61(2):504-8.
Urasaki, Y., Laco, G., Takebayashi, Y., Bailly, C., Kohlhagen, G., & Pommier, Y. (2001). Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site. Cancer Research, 61(2), 504-8.
Urasaki Y, et al. Use of Camptothecin-resistant Mammalian Cell Lines to Evaluate the Role of Topoisomerase I in the Antiproliferative Activity of the Indolocarbazole, NB-506, and Its Topoisomerase I Binding Site. Cancer Res. 2001 Jan 15;61(2):504-8. PubMed PMID: 11212241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site. AU - Urasaki,Y, AU - Laco,G, AU - Takebayashi,Y, AU - Bailly,C, AU - Kohlhagen,G, AU - Pommier,Y, PY - 2001/2/24/pubmed PY - 2001/3/3/medline PY - 2001/2/24/entrez SP - 504 EP - 8 JF - Cancer research JO - Cancer Res VL - 61 IS - 2 N2 - NB-506 is a topoisomerase I (top1) inhibitor in clinical trials. In this study, we used a series of camptothecin (CPT)-resistant cell lines with known top1 alterations. We show that three mutations in different domains of the top1 enzyme that confer CPT resistance also confer cross-resistance to NB-506. The CPT-resistant cell lines and corresponding mutations were: human prostate carcinoma cells DU-145/RC1 (mutation R364H), Chinese hamster fibroblasts DC3F/C10 (mutation G503S), and human leukemia CEM/C2 cells (N722S). This result suggests that NB-506 and CPT share a common binding site in the top1-DNA complex. We next used these three cell lines and their parental cells to study the relationship between top1 poisoning by NB-506 and antiproliferative activity. We found that the CPT-resistant cells were only 2-10-fold resistant to NB-506, which suggests that NB-506 targets other cellular processes/pathways besides top1. This conclusion was further supported by the limited cross-resistance of top1-deficient murine leukemia P388/CPT45 cells (2-fold). Cross-resistance was also limited for J-109,382, an isomer of NB-506 that does not intercalate into DNA, indicating that the non-top1-mediated antiproliferative activity of NB-506 is not attributable to DNA intercalation. Together, these data indicate that NB-506 and indolocarbazoles are promising agents to overcome CPT resistance. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11212241/Use_of_camptothecin_resistant_mammalian_cell_lines_to_evaluate_the_role_of_topoisomerase_I_in_the_antiproliferative_activity_of_the_indolocarbazole_NB_506_and_its_topoisomerase_I_binding_site_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11212241 DB - PRIME DP - Unbound Medicine ER -