| Autor: | Xavier Barlet, Cindy Mollard, Régine Mariage-Samson, Guilaine Gremy, Christine Couillault, Malika Lajémi, Esther Graudens, Eric Eveno, Patrick Zaborski, Dominique Piatier-Tonneau, Virginie Boulanger, Charles Auffray, Sandrine Imbeaud |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Drug
0303 health sciences Candidate gene Colorectal cancer media_common.quotation_subject Combination chemotherapy Drug resistance Biology medicine.disease Bioinformatics 3. Good health Gene expression profiling Irinotecan 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis medicine DNA microarray 030304 developmental biology media_common medicine.drug |
| Zdroj: | Genome Biology. 7:R19 |
| ISSN: | 1465-6906 |
| Popis: | Background: The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment. Results: Transcriptional profiles of clinical samples collected from CRC patients prior to their exposure to a combined chemotherapy of folinic acid, 5-fluorouracil and irinotecan were established using microarrays. Vigilant experimental design, power simulations and robust statistics were used to restrain the rates of false negative and false positive hybridizations, allowing successful discrimination between drug resistance and sensitivity states with restricted sampling. A list of 679 genes was established that intrinsically differentiates, for the first time prior to drug exposure, subsequently diagnosed chemo-sensitive and resistant patients. Independent biological validation performed through quantitative PCR confirmed the expression pattern on two additional patients. Careful annotation of interconnected functional networks provided a unique representation of the cellular states underlying drug responses. Conclusion: Molecular interaction networks are described that provide a solid foundation on which to anchor working hypotheses about mechanisms underlying in vivo innate tumor drug responses. These broad-spectrum cellular signatures represent a starting point from which by-pass chemotherapy schemes, targeting simultaneously several of the molecular mechanisms involved, may be developed for critical therapeutic intervention in CRC patients. The demonstrated power of this research strategy makes it generally applicable to other physiological and pathological situations. |
| Databáze: | OpenAIRE |
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