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Research Article: Development

Sequential oral 9-nitrocamptothecin and etoposide: a pharmacodynamic- and pharmacokinetic-based phase I trial

¹ H. Lee Moffitt Cancer Center and Research Institute, Departments of Interdisciplinary Oncology and Biochemistry and Molecular Biology, Experimental Therapeutics Program, University of South Florida, Tampa, Florida and ² University of Miami and Sylvester Cancer Center, Department of Medicine (Hematology/Oncology), Miami, Florida

Requests for reprints: Pamela N. Munster, Comprehensive Breast Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, SRB-2, Tampa, FL 33612-9416. Phone: 813-745-8948; Fax: 813-745-1984. E-mail: MunstePN{at}moffitt.usf.edu

Abstract

Purpose: Resistance to topoisomerase (topo) I inhibitors has been related to down-regulation of nuclear target enzyme, whereas sensitization to topo II inhibitors may result from induction of topo II by topo I inhibitors. Here, we evaluated a sequence-specific administration of a topo I inhibitor followed by a topo II inhibitor. Experimental Design: Twenty-five patients with advanced or metastatic malignancies were treated with increasing doses (0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mg/m²) of 9-nitrocamptothecin (9-NC) on days 1 to 3, followed by etoposide (100 or 150 mg/d) on days 4 and 5. At the maximally tolerated dose, 20 additional patients were enrolled. The median age was 60 years (range, 40–84 years). Endpoints included pharmacokinetic analyses of 9-NC and etoposide, and treatment-induced modulations of topo I and II expression in peripheral blood mononuclear cells. Results: Neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and fatigue were dose-limiting toxicities and occurred in six patients. Despite a median number of four prior regimens (range 1–12), 2 (4%) patients had an objective response and 13 (29%) patients had stable disease. In contrast to the expected modulation in topo I and II levels, we observed a decrease in topo II levels, whereas topo I levels were not significantly altered by 9-NC treatment. Conclusions: Sequence-specific administration of 9-NC and etoposide is tolerable and active. However, peripheral blood mononuclear cells may not be a predictive biological surrogate for drug-induced modulation of topo levels in tumor tissues and should be further explored in larger studies. [Mol Cancer Ther 2006;5(8):2130–7]

Grant support: Grant CA082533 MOPP P01.

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 1/23/06; revised 5/ 4/06; accepted 5/31/06.