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Cancer cell adaptation to chemotherapy
Federica Di Nicolantonio1, Stuart J Mercer, Louise A Knight
1Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK. federicadn@hotmail.com
BMC Cancer
|July 20, 2005
Summary
Human tumors adapt to chemotherapy rapidly, with gene expression changes occurring within days of treatment initiation. This rapid adaptation, observed in various cancer types, highlights the need for advanced predictive methods to improve chemotherapy response rates.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor resistance to chemotherapy is a significant clinical challenge.
- Mechanisms of resistance are often studied in cell lines due to difficulties with tumor-derived cells.
- Clonal selection has been the assumed driver of resistance in recurrent tumors.
Purpose of the Study:
- To investigate rapid molecular changes associated with chemotherapy resistance in human solid tumors.
- To assess gene and protein expression alterations in response to various anticancer agents.
- To evaluate the presence of these changes in pre- and post-chemotherapy biopsy samples.
Main Methods:
- Short-term cell culture (6 days) of cells from 47 human solid tumors (breast, ovarian, esophageal, colorectal) and 16 paired esophageal biopsies.
- Exposure of tumor cells and biopsies to a panel of anticancer agents including cisplatin, 5-fluorouracil, epirubicin, doxorubicin, paclitaxel, irinotecan, and topotecan.
- Analysis of gene expression using real-time quantitative PCR and protein levels via immunohistochemistry.
Main Results:
- Increased expression of multi-drug resistance gene 1 (MDR1) and its protein product P-gp was observed in esophageal biopsies after chemotherapy.
- Down-regulation of topoisomerase IIalpha (TOPOIIalpha) was noted in breast and ovarian carcinomas after doxorubicin exposure.
- Significant down-regulation of TOPOIIalpha was also observed in colorectal and ovarian tumors following topotecan exposure.
Conclusions:
- Human solid tumors can exhibit rapid up-regulation of resistance genes or down-regulation of target genes within days of chemotherapy initiation.
- Similar adaptive molecular changes are present in pre- and post-chemotherapy biopsy materials.
- Tumor-specific heterogeneity in response suggests the need for complex predictive methods beyond individual markers to enhance chemotherapy efficacy.