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Research Articles: Therapeutics

Efficacy of a nitric oxide–releasing nonsteroidal anti-inflammatory drug and cytotoxic drugs in human colon cancer cell lines in vitro and xenografts

¹ Preclinical Experimental Laboratory, Regina Elena Institute for Cancer Research, Rome, Italy; ² Department of Medical Oncology, Morgagni-Pierantoni Hospital and ³ Istituto Oncologico Romagnolo, Forlì, Italy; ⁴ Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; and ⁵ NicOx SA, Sophia-Antipolis, France

Requests for reprints: Wainer Zoli, Department of Medical Oncology, Morgagni-Pierantoni Hospital, Via Forlanini 34, 47100 Forlì, Italy. Phone: 39-0543-731622; Fax: 39-0543-731736. E-mail: w.zoli{at}ausl.fo.it

Abstract

We previously showed that NCX 4040 inhibits in vitro and in vivo tumor growth and induces apoptosis in human colon cancer cell lines. On the basis of these results, NCX 4040 antitumor activity in combination with 5-fluorouracil (5-FU) or oxaliplatin was evaluated in vitro and in vivo in human colon cancer models. The cytotoxicity of different NCX 4040 and 5-FU or oxaliplatin combination schemes was evaluated on a panel of colon cancer lines (LoVo, LoVo Dx, WiDr, and LRWZ) by the sulforhodamine B assay, and apoptosis was assessed by flow cytometry. NCX 4040 and 5-FU combination was always additive in vitro regardless of the scheme used. Sequential NCX 4040oxaliplatin treatment produced a strong synergism in three cell lines, with a ratio index ranging from 3.7 to 4. The synergistic effect was accompanied by apoptosis induction (up to 40%). In the in vivo experiments, xenografted mice were treated with the sequential combination of NCX 4040 and oxaliplatin, and apoptosis was evaluated immunohistochemically in excised tumors. Furthermore, in WiDr xenografts, this sequence caused a significantly higher reduction (60%) in tumor growth compared with single-drug treatments and produced extensive apoptotic cell death (15.3%), significantly higher (P < 0.01) than that observed in untreated tumors (2.7%) or in tumors treated with NCX 4040 (5.1%) or oxaliplatin (5.7%) alone. These data show that NCX 4040 sensitizes colon cancer cell lines to the effect of antitumor drugs and suggests that their combination could be useful for the clinical management of colon cancer. [Mol Cancer Ther 2006;5(4):919–26]

Grant support: Istituto Oncologico Romagnolo, Forlì, and Italian Ministry of Health 2004.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/22/05; revised 2/ 2/06; accepted 2/21/06.