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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.

journal_name

Int J Cancer

journal_title

International journal of cancer

authors

Nakajima TE,Yasunaga M,Kano Y,Koizumi F,Kato K,Hamaguchi T,Yamada Y,Shirao K,Shimada Y,Matsumura Y

doi

10.1002/ijc.23381

subject

Has Abstract

pub_date

2008-05-01 00:00:00

pages

2148-53

issue

eissn

0020-7136

issn

1097-0215

journal_volume

122

pub_type

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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.