Schedule-dependent cytotoxicity of 5-fluorouracil and irinotecan in p53 mutant human colon cancer.
J Exp Clin Cancer Res
; 26(2): 241-51, 2007 Jun.
Article
in En
| MEDLINE
| ID: mdl-17725105
ABSTRACT
IFL [irinotecan (CPT-11), 5-fluorouracil (5-FU), and folinic acid] is one of the treatments for metastatic colorectal cancer. We evaluated cytotoxic effects of a sequentially administered a combination of 5-FU with CPT-11 in human p53 mutant colon cancer. Sequential combination of 5-FU and CPT-11 in human colon cancer SW480 cells using a WST-8 colorimetric assay was studied. Cytotoxicity and cell cycle distribution for each drug were evaluated using an apoptosis assay and flow cytometry. Potential mechanisms of sequence-dependent cytotoxic effects were investigated using microarrays. Cytotoxicity of 5-FU (10, 100, 1000 microM) combined with subsequent use of CPT-11 (1 microM) was significantly greater than the reverse sequence of CPT-11 followed by 5-FU (p < 0.05). Following 24 hrs treatment with 5-FU (0.1-100 microM), no significant apoptosis was observed. In contrast, apoptosis was significantly induced after 24 hrs treatment with CPT-11 (1 and 10 microM). Flow cytometric analysis showed no significant difference in cell cycle distribution between different drug concentrations. We demonstrated up-regulation of 85 genes and down-regulation of 21 genes correlating with sequence-dependent cytotoxicities of 5-FU and CPT-11. The superiority of 5-FU-CPT-11 sequence was proven for p53 mutant colon cancer, SW480. Treatment with 5-FU followed by CPT-11 administration may be the optimal sequence for IFL treatment of metastatic colon cancers.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Camptothecin
/
Antineoplastic Combined Chemotherapy Protocols
/
Colonic Neoplasms
/
Fluorouracil
Limits:
Humans
Language:
En
Journal:
J Exp Clin Cancer Res
Year:
2007
Document type:
Article
Affiliation country: