PROJECT #4

Strategies To Predict Response To Topoisomerase Drug Therapy:  The ICT Bioassay.

Primary Reference:  Analysis of Topoisomerase I DNA complexes in patients administered topotecan.   Cancer Research 55:2097-2103

Abstract 

As part of a phase II clinical trial of topotecan, DNA breakage in vivo was measured by detecting covalent topoisomerase/DNA intermediates in peripheral blood. The ICT bioassay (for In vivo Complex of Topo) was used to assess topotecan activity in the peripheral blood of patients before, during and after infusion therapy.  The results can be summarized as follows.  1) The ICT bioassay is a specific, antibody based assay for topoisomerase I mediated DNA damage; topoisomerase I/DNA complex formation can be unambiguously monitored in the absence of topotecan to establish a basal level of endogenous enzyme action on DNA.  2) Infusion of topotecan significantly stimulated formation of covalent enzyme/DNA complexes; complexes were detected within 5 minutes post-infusion and increased over the course of a 30 minute treatment.  3) After termination of infusion, complex formation decreased by 3-4 fold within 30 minutes showing that cleavage complexes quickly reseal after drug withdrawal. 4) Formation of complexes varied widely between patients.  The ICT bioassay could be used to evaluate the effects of topoisomerase I inhibitors on target tissues, thus it may valuable in predicting response to these drugs.  By prescreening patients, we should be able to devise a strategy to eliminate likely non- responders while retaining patients that are likely to benefit from a topo-based therapy.  The primary goal for this research is to characterize and optimize strategies for mechanistic prescreening of patients.

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