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Annals of Oncology 2006 17(Supplement 5):v20-v24; doi:10.1093/annonc/mdj944
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© 2006 European Society for Medical Oncology

symposium article

In vitro basis for schedule-dependent interaction between gemcitabine and topoisomerase-targeted drugs in the treatment of colorectal cancer

S. N. Richter1,3, G. Cartei2, M. Nadai1, A. Trestin1,2, L. Barzon1, M. Palumbo3 and G. Palù1

1 Department of Histology, Microbiology and Medical Biotechnologies, University of Padova; 2 O. U. C. Medical Oncology, Busonera Hospital 1st floor, Istituto Oncologico Veneto (IOV) IRCCS, Padova; 3 Department of Pharmaceutical Sciences, University of Padova, Italy

Correspondence to: S. N. Richter, Department of Histology, Microbiology and Medicinal Biotechnologies, via Gabelli 63, University of Padova, Italy. Tel: +39-0498275711; Fax: +39-0498275711; E-mail: sara.richter{at}unipd.it

Background: While combination of gemcitabine with anti-topoisomerase poisons is routinely used in oncology, little is known on the biological interactions between these drugs.

Design: To understand the cellular basis for this association, we hypothesized an interaction of the two agents at the topoisomerase level. A real-time RT-PCR method was designed to quantify topoisomerase expression after treatment with gemcitabine (GEM) in two human colon adenocarcinoma cell lines. Efficacy of drugs as single agents and in combination was analyzed on the basis of their cytotoxic effects.

Results: We showed that a) gemcitabine induces expression of all major eukaryotic topoisomerases (I, II {alpha} and ß) at definite times after drug administration; b) cytotoxicity was more relevant when cells were treated with GEM and the topoisomerase poison within a short period of time. In particular synergistic effects were found when the anti-topoisomerase II agent was given 3 h after gemcitabine or when the anti-topoisomerase I drug was delivered 3 h before or after the antimetabolite.

Conclusions: These findings help explaining the effectiveness of the combined therapy GEM/topoisomerase poisons and suggest a drug administration protocol for clinical treatment.

Key words: antimetabolite, colorectal cancer, cytotoxicity, real time RT-PCR, synergism, topoisomerase poison


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