[Response of metastatic colorectal cancers to treatment with CPT11 (irinotecan): implications of the mismatched base repair system].
OBJECTIVE
The aim of our study was to assess the potential relationships between tumor responsiveness to CPT11, an analogue of camptothecin, which selectively inhibits DNA topoisomerase I, and the microsatellite instability, a feature 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 microsatellite status of repeated mononucleotide tracts present in the coding region of RII-TGFB, BAX, hMSH3 and hMSH6 genes.


RESULTS
A partial or minor response was observed in 9 patients, disease stabilization 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 expression. Four of the 31 tumors analyzed displayed intragenic microsatellite instability. We found a good correlation between inactivation of TGFB-RII, BAX or hMSH3 genes and tumor response to CPT-11 (P =0.002).


CONCLUSIONS
Our preliminary data suggest that intragenic microsatellite instability may influence tumor response to CPT-11 in patients with colorectal cancer.
Fallik
D
D
Laboratoire CNRS UMR 1598, Service de Gastroentérologie, Institut Gustave-Roussy, Camille-Desmoulins, Villejuif.
Sabourin
J C
JC
Borrini
F
F
Jacob
S
S
Boige
V
V
Praz
F
F
Ducreux
M
M
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D020137:Base Pair Mismatch; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002352:Carrier Proteins; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins; D006801:Humans; D000077146:Irinotecan; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D012189:Retrospective Studies
D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002166:Camptothecin