title: Topoisomerase I levels in white blood cells of patients with ovarian cancer treated with paclitaxel-cisplatin-topotecan in a phase I study.
abstract: Topotecan stabilizes the topoisomerase I (Topo I) cleavable complex. We measured Topo I levels in white blood cells of patients with ovarian cancer treated with topotecan. Topotecan was given i.v. daily x 5 q 3 weeks in combination with paclitaxel (1 day before topotecan) and cisplatin (just prior topotecan). Our aim was to correlate Topo I levels to pharmacokinetics and toxicity. Topo I levels were determined using Western blotting and were expressed relative to the Topo I level present in 10 microg cell lysate of the human IGROV1 ovarian cancer cell line. We found no correlation between Topo I levels and (non-)hematological toxicity. Topo I levels after the fifth topotecan infusion were significantly negatively correlated with the AUC of topotecan (R = -0.64, p = 0.026), in contrast with Topo I levels prior to (R = -0.25, p = 0.4) and after (R = -0.30, p = 0.3) the first topotecan infusion. Topo I levels after the fifth topotecan infusion (48 +/- 27%, mean +/- SD) were higher than Topo I levels prior to and after the first topotecan infusion (3.0 +/- 4.7 and 2.7 +/- 3.6%, respectively) (p = 0.001). In conclusion, we detected a significant inverse correlation between Topo I level and topotecan AUC at day 5, and we found increasing Topo I levels during a daily x 5 schedule of treatment with topotecan.
authors.affiliation: Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. APNSC@SLZ.nl
authors.forename: Nadja E
authors.initials: NE
authors.lastname: Schoemaker
authors.forename: Virginie M M
authors.initials: VM
authors.lastname: Herben
authors.forename: Laurina A
authors.initials: LA
authors.lastname: de Jong
authors.forename: Robert C A M
authors.initials: RC
authors.lastname: van Waardenburg
authors.forename: Dick
authors.initials: D
authors.lastname: Pluim
authors.forename: Wim W
authors.initials: WW
authors.lastname: ten Bokkel Huinink
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood* / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D015415:Biomarkers; D016179:Granulocyte Colony-Stimulating Factor; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D017239:Paclitaxel; D002945:Cisplatin