Journal article
Therapeutic synergy between irinotecan and 5-fluorouracil against human tumor xenografts
Clinical cancer research, Vol.10(3), pp.1121-1129
02/01/2004
DOI: 10.1158/1078-0432.CCR-0913-3
PMID: 14871992
Abstract
PURPOSEAlthough the combination of irinotecan and 5-Fluorouracil is clinically active, it is associated with significant toxicity and resistance. Studies were carried out to define the optimal dosage, sequence, and timing for the combination in mice bearing xenografted human tumors. EXPERIMENTAL DESIGNThe maximum tolerated dose of irinotecan and 5-Fluorouracil in combination was determined in nude mice. Therapeutic efficacy against established human colon carcinoma xenografts, HCT-8 and HT-29, and human head and neck squamous cell carcinoma xenografts, FaDu and A253, was determined using the rugs individually, simultaneously, and in sequence with various intervals in between. Treatments were i.v. weekly x 4. Immunohistochemical and reverse transcription-PCR measurements of relevant drug-metabolizing enzymes, apoptosis-related proteins, cell cycle distribution, cyclin A, and S phase fraction expression were carried out and compared with the therapeutic outcome. RESULTSThe maximum tolerated dose of irinotecan resulted in cure rates of 30% or less in all xenografts. No cures were achieved with FUra alone. Concurrent administration of irinotecan and FUra, or of FUra 24 h before irinotecan, resulted in cure rates of <20%, except for FaDu (60%). Administration of irinotecan 24 h before FUra resulted in the highest cure rates, 80% in HCT-8, 0% in HT-29, 100% in FaDu, and 10% in A253. CONCLUSIONSThe optimal therapeutic synergy was achieved when irinotecan was administered 24 h before 5-Flurouracil. Sensitivity to this combination was associated with poor differentiation status, higher cyclin A index, recruitment of cells into S phase, and induction of Bax expression and apoptosis.
Details
- Title: Subtitle
- Therapeutic synergy between irinotecan and 5-fluorouracil against human tumor xenografts
- Creators
- Rami G Azrak - Roswell Park Cancer InstituteShousong CaoHarry K SlocumKároly TóthFarukh A DurraniMing-biao YinLakshmi PendyalaWanghai ZhangHoward L McLeodYoucef M Rustum
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.10(3), pp.1121-1129
- DOI
- 10.1158/1078-0432.CCR-0913-3
- PMID
- 14871992
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 02/01/2004
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359584902771
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