Cell kinetics-dependent antitumor effect of irinotecan hydrochloride induced by the synchronizing effect of hydroxyurea: cell kinetics and dosing time.
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.
Akagi
Takanori
T
Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
Ushinohama
Kazami
K
Kage
Yuki
Y
Ishizaki
Takashi
T
Makinosumi
Tomoko
T
Yamauchi
Atsushi
A
Taguchi
Yukie
Y
Inoue
Kouichi
K
Yukawa
Eiji
E
Higuchi
Shun
S
Ohdo
Shigehiro
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004950:Esterases / Q000378:metabolism; D006918:Hydroxyurea / Q000008:administration & dosage / Q000494:pharmacology*; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D012510:Sarcoma 180 / Q000188:drug therapy / Q000473:pathology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D004247:DNA; D004950:Esterases; D006918:Hydroxyurea; D002166:Camptothecin