title: Synergistic antitumor activity of the novel SN-38-incorporating polymeric micelles, NK012, combined with 5-fluorouracil in a mouse model of colorectal cancer, as compared with that of irinotecan plus 5-fluorouracil.
abstract: The authors reported in a previous study that NK012, a 7-ethyl-10-hydroxy-camptothecin (SN-38)-releasing nano-system, exhibited high antitumor activity against human colorectal cancer xenografts. This study was conducted to investigate the advantages of NK012 over irinotecan hydrochloride (CPT-11) administered in combination with 5-fluorouracil (5FU). The cytotoxic effects of NK012 or SN-38 (an active metabolite of CPT-11) administered in combination with 5FU was evaluated in vitro in the human colorectal cancer cell line HT-29 by the combination index method. The effects of the same drug combinations was also evaluated in vivo using mice bearing HT-29 and HCT-116 cells. All the drugs were administered i.v. 3 times a week; NK012 (10 mg/kg) or CPT11 (50 mg/kg) was given 24 hr before 5FU (50 mg/kg). Cell cycle analysis in the HT-29 tumors administered NK012 or CPT-11 in vivo was performed by flow cytometry. NK012 exerted more synergistic activity with 5FU compared to SN-38. The therapeutic effect of NK012/5FU was significantly superior to that of CPT-11/5FU against HT-29 tumors (p = 0.0004), whereas no significant difference in the antitumor effect against HCT-116 tumors was observed between the 2-drug combinations (p = 0.2230). Cell-cycle analysis showed that both NK012 and CPT-11 tend to cause accumulation of cells in the S phase, although this effect was more pronounced and maintained for a more prolonged period with NK012 than with CPT-11. Optimal therapeutic synergy was observed between NK012 and 5FU, therefore, this regimen is considered to hold promise of clinical benefit, especially for patients with colorectal cancer.
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takako Eguchi
authors.initials: TE
authors.lastname: Nakajima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.forename: Ken
authors.initials: K
authors.lastname: Kato
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D011108:Polymers; D014183:Transplantation, Heterologous
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D011108:Polymers; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin