S-phase modulation by irinotecan : pilot studies in advanced solid tumors

• Published in: Cancer chemotherapy and pharmacology Vol. 56; no. 5; pp. 447 - 454
• Main Authors: RAMNATH, N, KHUSHALANI, N, JAVLE, M. M, BERDZIK, J, CREAVEN, P. J, RUSTUM, Y. M, TOTH, K, LITWIN, A. M, INTENGAN, M. E, SLOCUM, H. K, PENDYALA, L, SMITH, P. F, STEWART, C. C, HOFFMAN, J. L
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-11-2005; Springer Nature B.V
• Subjects: Adenocarcinoma - drug therapy; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacokinetics; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biopsy; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Camptothecin - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Squamous Cell - drug therapy; Cyclin A - analysis; Cyclin A - metabolism; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacokinetics; Female; Fluorouracil - administration & dosage; Fluorouracil - pharmacokinetics; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - pathology; Humans; Male; Maximum Tolerated Dose; Medical sciences; Pharmacology. Drug treatments; Respiratory Tract Neoplasms - drug therapy; Respiratory Tract Neoplasms - pathology; S Phase - drug effects; Antineoplastic agent; Solid tumor; Gemcitabine; 5-Fluorouracil; Enzyme; Fluoropyrimidine derivatives; Transferases; DNA topoisomerase; Enzyme inhibitor; Malignant tumor; Thymidylate synthase; Irinotecan; Isomerases; Antimetabolic; Methyltransferases; Modulation; S Phase; Cell cycle; Pyrimidine derivatives; Advanced stage; Fluorine Organic compounds; Pyrimidine nucleoside; S-phase modulation; Fluorouracil
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-004-0951-6

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.