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

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

Research output: Contribution to journalArticle

9 Scopus citations

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 24h 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.

Original languageEnglish (US)
Pages (from-to)447-454
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume56
Issue number5
DOIs
Publication statusPublished - Nov 1 2005

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Ramnath, N., Khushalani, N., Toth, K., Litwin, A. M., Intengan, M. E., Slocum, H. K., ... Rustum, Y. M. (2005). S-phase modulation by irinotecan: Pilot studies in advanced solid tumors. Cancer Chemotherapy and Pharmacology, 56(5), 447-454. https://doi.org/10.1007/s00280-004-0951-6