title: A phase I and pharmacodynamic study of sequential topotecan and etoposide in patients with relapsed or refractory acute myelogenous and lymphoblastic leukemia.
abstract: We designed a pharmacokinetic and pharmacodynamic phase I study of sequential topotecan (2.55-6.3mg/m2) by 72h infusion followed by five daily doses of etoposide for patients with refractory acute leukemia based upon synergistic anti-tumor activity of topoisomerase I and II inhibitors in vitro. Eight of the 29 patients achieved bone marrow aplasia and two patients achieved clinical remission. Common grade 3-4 toxicities included hepatic and gastrointestinal dysfunction, and correlated with increased steady-state plasma topotecan concentration. The predicted up-regulation of topoisomerase II activity by topoisomerase I inhibition was not observed at this dose and schedule and may provide insight into the modest anti-leukemia activity of the regimen.
authors.affiliation: Department of Medicine, University Hospitals of Cleveland, Cleveland, OH 44106, USA. bxc12@po.cwru.edu
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Cooper
authors.forename: Erin
authors.initials: E
authors.lastname: Donaher
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
authors.forename: Sylvan B
authors.initials: SB
authors.lastname: Green
authors.forename: David M
authors.initials: DM
authors.lastname: Gosky
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Rosenthal
authors.forename: Sosamma J
authors.initials: SJ
authors.lastname: Berger
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ingalls
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology; D001853:Bone Marrow / Q000201:enzymology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016609:Neoplasms, Second Primary / Q000188:drug therapy / Q000201:enzymology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D005047:Etoposide; D019772:Topotecan; D004250:DNA Topoisomerases, Type II