The antitumor activity of NK012, an SN-38-incorporating micelle, in combination with bevacizumab against lung cancer xenografts.

Abstract

BACKGROUND:

It has been demonstrated that NK012, a novel 7-ethyl-10-hydroxycamptothecin (SN-38)-incorporating polymeric micelle, exerts significantly more potent antitumor activity against various human tumor xenografts than irinotecan (CPT-11) (a water-soluble prodrug of SN-38). Combination therapy of anticancer agents with bevacizumab (Bv), an anti-vascualr endothelial growth factor humanized monoclonal antibody, has more potently inhibited tumor growth than either agent alone. In the current study, the authors examined the antitumor effect of NK012 in combination with Bv against human lung cancer.

METHODS:

Nude mice bearing lung adenocarcinoma (PC-14 or A549 xenografts) were administered NK012 at SN-38-equivalent doses of 5 mg/kg or 30 mg/kg in combination with or without Bv at 5 mg/kg. CPT-11 at a dose of 66.7 mg/kg was administered with or without Bv at a dose of 5 mg/kg in the same experimental model. To evaluate interaction with Bv, the pharmacokinetics and microvessel density in tumors that were treated on each regimen were analyzed.

RESULT:

In vitro, the growth-inhibitory effect of NK012 was 50-fold more potent than that of CPT-11 and was almost equivalent to that of SN-38. In vivo studies revealed that the combination of NK012 plus Bv had significantly greater antitumor activity against human lung cancer xenografts compared with NK012 alone (PC-14, P=.0261; A549, P<.001). The pharmacokinetic profile of NK012 revealed that coadministration of Bv did not interfere with the accumulation of NK012.

CONCLUSIONS:

In this study, significant antitumor activity was noted with NK012 in combination with Bv against lung cancer cells. The current results warrant the clinical evaluation of NK012 in lung cancer.

• Authors: Hirotsugu Kenmotsu, Masahiro Yasunaga, Koichi Goto, Tatsuya Nagano, Jun-ichiro Kuroda, Yoshikatsu Koga, Amane Takahashi, Yutaka Nishiwaki, Yasuhiro Matsumura
• Journal: Cancer (Cancer) Vol. 116 Issue 19 Pg. 4597-604 (Oct 01 2010) ISSN: 0008-543X [Print] United States
• PMID: 20572031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 American Cancer Society.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Phytogenic
• Micelles
• Bevacizumab
• Irinotecan
• Camptothecin

Topics

• Adenocarcinoma (drug therapy, metabolism)
• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacokinetics)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Phytogenic (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab
• Camptothecin (analogs & derivatives, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Female
• Humans
• Irinotecan
• Lung Neoplasms (drug therapy, metabolism)
• Mice
• Mice, Inbred BALB C
• Micelles
• Xenograft Model Antitumor Assays