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

✍ Scribed by Takako Eguchi Nakajima; Masahiro Yasunaga; Yasuhiko Kano; Fumiaki Koizumi; Ken Kato; Tetsuya Hamaguchi; Yasuhide Yamada; Kuniaki Shirao; Yasuhiro Shimada; Yasuhiro Matsumura

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: French
• Weight: 598 KB
• Volume: 122
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.23381

✦ Synopsis

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. © 2008 Wiley‐Liss, Inc.