Thymidine Selectively Enhances Growth Suppressive Effects of Camptothecin/Irinotecan inMSI+ Cells andTumors Containing aMutationof MRE11

Abstract

Purpose: DNA synthesis inhibitors and damaging agents are widely used in cancer therapy; however, sensitivity of tumors to such agents is highly variable. The response of tumor cells in culture to these agents is strongly influenced by the status of DNA damage response pathways. Here, we attempt to exploit the altered response of mismatch repair (MMR)-deficient colon cancer cells and tumors to camptothecin or irinotecan and thymidine by combining them to improve therapeutic response. Experimental Design: A panel of colon cancer cell lines was assayed for response to camptothecin-thymidine combinations by measuring colony formation, cell cycle distribution, and senescence. Cell strains defective in p53, p21, or Mre11were used in these assays to investigate the role of these cell cycle regulators.The in vivo antitumor response of xenografts to irinotecan and thymidine combinations was assessed in nude mice. Results: Camptothecin-thymidine combinations suppress colony formation of MMR-deficient tumor cells 10- to 3,000-fold relative to that obtained with camptothecin alone and significantly reduce the concentrations of the agents required to induce late S/G2 arrest and senescence. Sensitivity is not a direct result of MMR, p53, or p21status. However MMR-deficient cell lines containing an intronic frameshift mutation of MRE11 show greatest sensitivity to these agents. Increased sensitivity to this combination is also evident in vivo as thymidine enhances irinotecan-induced growth suppression of MMR-deficient tumors carrying the MRE11 mutation in mouse xenografts. Conclusion: Irinotecan-thymidine combinations may be particularly effective when targeted toMSI+ tumors containing this readily detectable MRE11mutation.