Topoisomerase I-DNA covalent complexes in human colorectal cancer xenografts with different p53 and microsatellite instability status: Relation with their sensitivity to CTP-11

The topoisomerase I poison CPT-11 has proved efficient for the treatment of untreated metastatic colorectal cancels (CRC) and those refractory to fluo ropyrimidines. However, the interpatient variability is important. A previo us in vitro study suggested that measurements of the level of topoisomerase I-DNA intermediates trapped by camptothecin may be useful to estimate the chemosensitivity of colon carcinoma cell lines. To verify this hypothesis, we developed an immuno-assay to detect covalent topoisomerase I-DNA complex es in a series of human colorectal cancers xenografted in node mice. Six hu man CRCs were selected for their distinctive p53 and microsatellite instabi lity (MSI) status. Tumour lysates, prepared from mice untreated or treated with CPT-11, were fractionated onto CsCl gradients to separate free and DNA -bound topoisomerase I by centrifugation. Interestingly, significant levels of DNA-topoisomerase I complexes weve detected in the tumours most respons ive to the treatment with CPT-II, irrespective of their MSI and p53 phenoty pes. Our in vivo study fully agrees with the predictions from the in vitro data indicating that evaluation of topoisomerase I-DNA complexes would be u seful to predict the response of CRC to a treatment with CPT-11.