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

Authors

  • Hirotsugu Kenmotsu MD,

    1. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
    2. Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Masahiro Yasunaga MD, PhD,

    1. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Koichi Goto MD, PhD,

    1. Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Tatsuya Nagano MD,

    1. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Jun-ichiro Kuroda MD, PhD,

    1. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Yoshikatsu Koga MD PhD,

    1. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Amane Takahashi MD,

    1. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Yutaka Nishiwaki MD, PhD,

    1. Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
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  • Yasuhiro Matsumura MD, PhD

    Corresponding author
    1. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan
    • Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-City, Chiba, 277-8577, Japan
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    • Fax: (011) 81-7134-6866


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. Cancer 2010. © 2010 American Cancer Society.

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