BACKGROUND: Use of irinotecan (CPT-11) as second-line therapy for metastatic colorectal cancer has shown some promise in cases where 5-fluorouracil (5-FU) has failed. Cross-resistance to both drugs may however be a potential clinical problem. The cellular response to CPT-11 was investigated in two human colon cancer cell lines that demonstrate a differential response to 5-FU. MATERIALS AND METHODS: Cell cycle progression, clonogenic survival, DNA damage checkpoint activation, apoptosis induction and senescence development were assessed during 48 hours of treatment and 72 hours of recovery. RESULTS: Both cell lines had similar cellular response patterns to CPT-11. Growth inhibition, loss of clonogenicity, ataxia telangiectasia mutated (ATM) activation, H2AX phosphorylation, TP53 stabilization, CDKN1A induction, G2/M arrests, endoreduplication, negligible cell death and appearance of a senescence-associated beta-galactosidase phenotype were observed. CONCLUSION: Cross-resistance to 5-FU and CPT-11 was not demonstrated. The appearance of a senescence phenotype in response to CPT-11 treatment may have potential clinical relevance for treatment regimens.
BACKGROUND: Use of irinotecan (CPT-11) as second-line therapy for metastatic colorectal cancer has shown some promise in cases where 5-fluorouracil (5-FU) has failed. Cross-resistance to both drugs may however be a potential clinical problem. The cellular response to CPT-11 was investigated in two humancolon cancer cell lines that demonstrate a differential response to 5-FU. MATERIALS AND METHODS: Cell cycle progression, clonogenic survival, DNA damage checkpoint activation, apoptosis induction and senescence development were assessed during 48 hours of treatment and 72 hours of recovery. RESULTS: Both cell lines had similar cellular response patterns to CPT-11. Growth inhibition, loss of clonogenicity, ataxia telangiectasia mutated (ATM) activation, H2AX phosphorylation, TP53 stabilization, CDKN1A induction, G2/M arrests, endoreduplication, negligible cell death and appearance of a senescence-associated beta-galactosidase phenotype were observed. CONCLUSION: Cross-resistance to 5-FU and CPT-11 was not demonstrated. The appearance of a senescence phenotype in response to CPT-11 treatment may have potential clinical relevance for treatment regimens.
Authors: María Angel García; Esther Carrasco; Margarita Aguilera; Pablo Alvarez; Carmen Rivas; Joaquin María Campos; Jose Carlos Prados; Miguel Angel Calleja; Mariano Esteban; Juan Antonio Marchal; Antonia Aránega Journal: PLoS One Date: 2011-08-24 Impact factor: 3.240