Cellular response to irinotecan in colon cancer cell lines showing differential response to 5-fluorouracil.
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.


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.


CONCLUSIONS
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.
The Pathology Clinic, Rikshospitalet Medical Center, 0027 Oslo, Norway.
Kristiane
K
Haug
K Liza
KL
Kravik
Paula M
PM
De Angelis
D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan
D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin