Leukemia Research 29 (2005) 785–791 Cytotoxic effects of novel amphiphilic dimers consisting of 5-fluorodeoxyuridine and arabinofuranosylcytosine in cross-resistant H9 human lymphoma cells Philipp Saiko a, b , Zsuzsanna Horvath a, b , Christoph Illmer a , Sibylle Madlener a , Wolfgang Bauer a , Thomas Hoechtl a , Natascha Erlach c , Michael Grusch c , Georg Krupitza d , Robert M. Mader e , Walter Jaeger f , Herbert Schott g , Ram P. Agarwal h , Monika Fritzer-Szekeres a , Thomas Szekeres a, ∗ a Clinical Institute of Medical & Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria b Center of Excellence in Clinical and Experimental Oncology (CLEXO) of the Medical University of Vienna, Austria c Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria d Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria e Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria f Department of Pharmaceutical Chemistry, Faculty of Natural Sciences and Mathematics, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria g Department of Organic Chemistry, Faculty of Chemistry and Pharmacy, University of Tuebingen, Auf der Morgenstelle 18, 72076 Tuebingen, Germany h Department of Medicine, Division of Hematology/Oncology, University of Miami, 1600 N.W. 10th Avenue, Miami, FL 33136, USA Received 6 September 2004; accepted 17 December 2004 Available online 19 February 2005 Abstract Various amphiphilic heterodinucleoside phosphates have recently been synthesized in order to overcome drug resistance. These agents contain 5-fluorodeoxyuridine (5-FdUrd) and arabinofuranosylcytosine (Ara-C). We now investigated the action of two of these novel dimers (# 2 and # 10) in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. The dimers were compared with 5-FdUrd and Ara-C for growth inhibition, apoptosis induction, and cell-cycle effects. No significant difference in the cytotoxicity of dimer # 2 could be observed between sensitive and 5-FdUrd/Ara-C cross-resistant H9 cells (IC 50 values of 220 nM and 200 nM, respectively), indicating that further studies with this compound are warranted. © 2005 Elsevier Ltd. All rights reserved. Keywords: Arabinofuranosylcytosine; 5-Fluorodeoxyuridine; Lymphoma; Cross-resistance; Apoptosis; Cell-cycle 1. Introduction 5-Fluorouracil (5-FU) is a pyrimidine analogue with the capacity to inhibit the biosynthesis of pyrimidine nu- cleotides. Following rapid transport into the cell, a signif- icant amount of the drug is converted by ribosylation and phosphorylation reactions into three main metabolites, two of which, fluorouridine triphosphate (5-FUTP) and fluo- rodeoxyuridine monophosphate (5-FdUMP), are known to ∗ Corresponding author. Tel.: +43 1 40400x5365; fax: +43 1 320 33 17. E-mail address: thomas.szekeres@meduniwien.ac.at (T. Szekeres). be active. 5-FUTP and 5-FdUMP are being further me- tabolized and cause inhibition of RNA and DNA synthe- sis. However, the development of drug resistance remains one of the major problems in anticancer chemotherapy. Several mechanisms have been hypothesized for observed resistance to 5-FU in tumor cells. These include loss or decreased ac- tivity of the key enzyme required for its activation, increased clearance, and overproduction of thymidylate synthase (ac- quired resistance) through gene amplification, overexpres- sion, or mutation [1]. In attempts to circumvent resistance to 5-FU by tumor cells, a number of modulators have been 0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2004.12.015