Responsiveness of metastatic colorectal cancers to chemotherapy with CPT11(irinotecan): possible role of the DNA mismatch repair system

Aims - The aim of our study was to assess the potential relationships betwe en tumor responsiveness to CPT11, an analogue of camptothecin, which select ively inhibits DNA topoisomerase I, and the microsatellite instability, a F eature of tumors with DNA mismatch repair defect. Methods - We designed a retrospective clinical study including 35 patients with metastatic colorectal cancer treated with CPT11, for which we analyzed the expression of hMLH1 and hMSH2 in the tumor and determined microsatelli te status of repeated mononucleotide tracts present in the coding region of RII-TGF beta, BAX, hMSH3 and hMSH6 genes. Results-A partial or minor response was observed in 9 patients, disease sta bilization in 14 patients and progression in 12 patients. Staining of hMLH1 was undetectable in 2 of the 35 tumors, while only 1 tumor lacked hMSH2 ex pression. Four of the 31 tumors analyzed displayed intragenic microsatellit e instability. We found a good correlation between inactivation of TGF beta -RII, BAX or hMSH3 genes and tumor response to CPT-11 (P = 0.002). Conclusion - Our preliminary data suggest that intragenic microsatellite in stability may influence tumor response to CPT-11 in patients with colorecta l cancer.