1. ¹Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
2. ²Department of Internal Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
3. ³Division of General Dermatology, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
4. ⁴Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
5. ⁵Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria

Correspondence: Dr Christian Joukhadar, Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: christian.joukhadar@meduniwien.ac.at

Received 28 February 2006; Revised 21 February 2007; Accepted 22 February 2007; Published online 17 May 2007.

Abstract

This study compares the antineoplastic potential of a novel treatment strategy combining cell cycle inhibitor-779 (CCI-779) plus dacarbazine (DTIC) versus DTIC monotreatment, the current chemotherapeutic mainstay in combating metastatic melanoma. A controlled four-group parallel study design comprising 24–40 mice per tumor cell line was used in a severe combined immunodeficiency (SCID)-mouse xenotransplantation model. SCID mice were injected with 518A2, Mel-JUSO, or 607B human melanoma cells. After they developed tumors, mice received daily CCI-779 or solvent over 14 days. From treatment day 4–8 mice were additionally injected with DTIC or saline. Treatment with CCI-779 plus DTIC was superior to single agent DTIC in two out of three cell lines (P<0.05). The tumor weight reduction was 4417 and 616% compared with DTIC monotreatment in Mel-JUSO and 607B melanomas, respectively (P<0.05). In contrast, in 518A2 xenotransplants, CCI-779 plus DTIC treatment was as effective as DTIC monotreatment. CCI-779 monotherapy exerted no statistically significant antitumor effect. Collectively, these data indicate that CCI-779 has the potential to increase the chemotherapeutic efficacy, as the combination of CCI-779 plus DTIC proved to be more efficacious compared to DTIC monotherapy in two out of three melanoma cell lines in vivo.