title: S-phase modulation by irinotecan: pilot studies in advanced solid tumors.
abstract: Two studies of irinotecan (CPT-11) followed 24 h later by an antimetabolite were conducted. The objectives of the studies were: (1) to determine whether the increase in S-phase in tumor cells seen 24 h after CPT-11 administration in animal studies is seen in advanced solid tumors in patients, (2) to determine the dose of CPT-11 required to produce this effect, (3) to compare two methods (immunohistochemistry, IHC, for cyclin A, and DNA flow cytometry, FC) for evaluating S-phase in tumor biopsies from patients, and (4) to establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of CPT-11, given 24 h before gemcitabine (GEM, 1000 mg/m(2)). In one study CPT-11 was followed 24 h later by 5-fluorouracil (5-FU), 400 mg/m(2) per week for 4 weeks every 6 weeks. Tumor biopsies were obtained before and 24 h after CPT-11 administration before administration of 5-FU and assayed for S-phase by IHC for cyclin A and by FC. The starting dose of CPT-11 was 80 mg/m(2) per week with subsequent exploration of 40 and 60 mg/m(2) per week to establish the dose-effect relationship of the increase in tumor cells in S-phase. In the second study, CPT-11 was given 24 h before GEM 1000 mg/m(2) per week for 2 weeks every 3 weeks. Doses of 20-80 mg/m(2) were explored to establish the MTD and DLT and to study tumor cell S-phase in selected patients. CPT-11 80 mg/m(2) produced a mean increase in S-phase by IHC for cyclin A of 137%. Lesser increases were seen with 40 and 60 mg/m(2). CPT-11 followed 24 h later by 5-FU 400 mg/m(2) per week for 4 weeks was well tolerated. In the study of CPT-11 followed by GEM 1000 mg/m(2), 60 mg/m(2) of CPT-11 was the MTD.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. nithya.ramnath@roswellpark.org
authors.forename: N
authors.initials: N
authors.lastname: Ramnath
authors.forename: N
authors.initials: N
authors.lastname: Khushalani
authors.forename: K
authors.initials: K
authors.lastname: Toth
authors.forename: A M
authors.initials: AM
authors.lastname: Litwin
authors.forename: M E
authors.initials: ME
authors.lastname: Intengan
authors.forename: H K
authors.initials: HK
authors.lastname: Slocum
authors.forename: L
authors.initials: L
authors.lastname: Pendyala
authors.forename: P F
authors.initials: PF
authors.lastname: Smith
authors.forename: C C
authors.initials: CC
authors.lastname: Stewart
authors.forename: J L
authors.initials: JL
authors.lastname: Hoffman
authors.forename: M M
authors.initials: MM
authors.lastname: Javle
authors.forename: J
authors.initials: J
authors.lastname: Berdzik
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001706:Biopsy; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D019925:Cyclin A / Q000032:analysis / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D012142:Respiratory Tract Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016196:S Phase / Q000187:drug effects*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D019925:Cyclin A; D003841:Deoxycytidine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin; D000093542:Gemcitabine