Effect of carboxylesterase inhibition on the anti-tumour effects of irinotecan.
Irinotecan (CPT-11) is an important anti-cancer agent activated by carboxylesterase (CE). Treatment with CPT-11 may be associated with severe adverse effects, however, so determining the optimal dose would greatly benefit patients. We investigated the relationship between the anti-tumour effects of CPT-11 and CE concentration using bis-p-nitrophenylphosphate (BNPP), a specific inhibitor of CE, in nude mice with xenograft tumours. Initial experiments showed that the optimal dose of CPT-11 was 100 mg/kg. This dose was then used to study the anti-tumour effects of CPT-11 with and without BNPP. A direct correlation was found between the dose of administered BNPP and the growth rate of the tumour, demonstrating that the anti-tumour effects of CPT-11 were related to the CE concentration. Measuring the concentration of CE may allow the optimum dose of CPT-11 to be determined, opening up the possibility of individualized chemotherapy programmes.
Morishita
Y
Y
Department of Digestive Surgery, Nihon University School of Medicine, Itabashi-Ku, Tokyo, Japan. myukie@med.nihon-u.ac.jp
Fujii
M
M
Kasakura
Y
Y
Takayama
T
T
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D043182:Carboxylesterase / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D043182:Carboxylesterase; D002166:Camptothecin