S-phase modulation by irinotecan: pilot studies in advanced solid tumors |
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Authors: | N Ramnath N Khushalani K Toth A M Litwin M E Intengan H K Slocum L Pendyala P F Smith C C Stewart J L Hoffman M M Javle J Berdzik P J Creaven Y M Rustum |
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Institution: | (1) Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA;(2) Department of Medicine, Veterans Administration Medical Center, Buffalo, NY, USA;(3) Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA;(4) Department of Diagnostic Radiology, Roswell Park Cancer Institute, Buffalo, NY, USA;(5) Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA;(6) Tissue Procurement Facility, Roswell Park Cancer Institute, Buffalo, NY, USA;(7) Department of Flow Cytometry, Roswell Park Cancer Institute, Buffalo, NY, USA;(8) Science Administration, Roswell Park Cancer Institute, Buffalo, NY, USA |
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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/m2). In one study CPT-11 was followed 24 h later by 5-fluorouracil (5-FU), 400 mg/m2 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/m2 per week with subsequent exploration of 40 and 60 mg/m2 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/m2 per week for 2 weeks every 3 weeks. Doses of 20–80 mg/m2 were explored to establish the MTD and DLT and to study tumor cell S-phase in selected patients. CPT-11 80 mg/m2 produced a mean increase in S-phase by IHC for cyclin A of 137%. Lesser increases were seen with 40 and 60 mg/m2. CPT-11 followed 24 h later by 5-FU 400 mg/m2 per week for 4 weeks was well tolerated. In the study of CPT-11 followed by GEM 1000 mg/m2, 60 mg/m2 of CPT-11 was the MTD.This work was presented in part at the 14th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Frankfurt, Germany, November 2002. |
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Keywords: | Irinotecan 5-Fluorouracil Gemcitabine S-phase modulation |
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