Cell kinetics-dependent antitumor effect of irinotecan hydrochloride induced by the synchronizing effect of hydroxyurea: Cell kinetics and dosing time

Takanori Akagi, Kazami Ushinohama, Yuki Kage, Takashi Ishizaki, Tomoko Makinosumi, Atsushi Yamauchi, Yukie Taguchi, Kouichi Inoue, Eiji Yukawa, Shun Higuchi, Shigehiro Ohdo

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Influence of hydroxyurea (HU) on the antitumor effect of irinotecan hydrochloride (CPT-11) was investigated in ICR male mice transplanted with sarcoma 180 cells (S-180). A single dose of CPT-11 (100 mg/kg) was injected at various times after a single dose of HU (300 mg/kg). The relative tumor weight varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The higher antitumor effect of CPT-11 was observed when DNA synthesis of S-180 cells increased (20 hr), and the lower effect was observed when the DNA synthesis decreased (0 hr). The loss of body weight also varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The toxicity of CPT-11 was higher when the inhibitory effect of HU on DNA synthesis of bone marrow cells was stronger (15 hr), and the lower toxicity was observed when the inhibitory effect was not observed (0 hr). The plasma SN-38 concentration at 2 hr after CPT-11 injection was higher at 20 hr after HU injection than at 0 hr after HU injection. The difference in plasma esterase activity between 0 hr and 20 hr after HU injection was regarded as the mechanism underlying the dosing time-dependent difference of the SN-38 concentration. These experiments suggest that HU can produce a different phase of cell cycle between tumor cells and normal cells. This leads to increase the antitumor effect of CPT-11 without increasing the adverse effect of the drug. It is essential to consider the dosing time in the two-drug combination therapy.

Original languageEnglish
Pages (from-to)1183-1197
Number of pages15
JournalLife Sciences
Volume72
Issue number10
DOIs
Publication statusPublished - Jan 24 2003

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint Dive into the research topics of 'Cell kinetics-dependent antitumor effect of irinotecan hydrochloride induced by the synchronizing effect of hydroxyurea: Cell kinetics and dosing time'. Together they form a unique fingerprint.

  • Cite this

    Akagi, T., Ushinohama, K., Kage, Y., Ishizaki, T., Makinosumi, T., Yamauchi, A., Taguchi, Y., Inoue, K., Yukawa, E., Higuchi, S., & Ohdo, S. (2003). Cell kinetics-dependent antitumor effect of irinotecan hydrochloride induced by the synchronizing effect of hydroxyurea: Cell kinetics and dosing time. Life Sciences, 72(10), 1183-1197. https://doi.org/10.1016/S0024-3205(02)02363-9