Abstract
BackgroundTumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Studies of human tumors show that cells adapt to chemotherapy, but it has been largely assumed that clonal selection leads to the resistance of recurrent tumors.MethodsCells derived from 47 tumors of breast, ovarian, esophageal, and colorectal origin and 16 paired esophageal biopsies were exposed to anticancer agents (cisplatin; 5-fluorouracil; epirubicin; doxorubicin; paclitaxel; irinotecan and topotecan) in short-term cell culture (6 days). Real-time quantitative PCR was used to measure up- or down-regulation of 16 different resistance/target genes, and when tissue was available, immunohistochemistry was used to assess the protein levels.ResultsIn 8/16 paired esophageal biopsies, there was an increase in the expression of multi-drug resistance gene 1 (MDR1) following epirubicin + cisplatin + 5-fluorouracil (ECF) chemotherapy and this was accompanied by increased expression of the MDR-1 encoded protein, P-gp. Following exposure to doxorubicin in vitro, 13/14 breast carcinomas and 9/12 ovarian carcinomas showed >2-fold down-regulation of topoisomerase IIα (TOPOIIα). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIα in 6/7 colorectal tumors and 8/10 ovarian tumors.ConclusionThis study suggests that up-regulation of resistance genes or down-regulation in target genes may occur rapidly in human solid tumors, within days of the start of treatment, and that similar changes are present in pre- and post-chemotherapy biopsy material. The molecular processes used by each tumor appear to be linked to the drug used, but there is also heterogeneity between individual tumors, even those with the same histological type, in the pattern and magnitude of response to the same drugs. Adaptation to chemotherapy may explain why prediction of resistance mechanisms is difficult on the basis of tumor type alone or individual markers, and suggests that more complex predictive methods are required to improve the response rates to chemotherapy.
Highlights
Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient
We have previously shown development of such resistance to combination chemotherapy in tumor-derived cells from matched biopsies collected from breast cancer patients before and after administration of doxorubicincontaining chemotherapy [2]
Chemotherapy-induced changes in mRNA levels in biopsy material Figures 1a–e illustrate changes to IC50 μM values in preand post chemotherapy ovarian tumor-derived cells tested with a variety of chemotherapeutic agents
Summary
Tumor resistance to chemotherapy may be present at the beginning of treatment, develop during treatment, or become apparent on re-treatment of the patient. The mechanisms involved are usually inferred from experiments with cell lines, as studies in tumor-derived cells are difficult. Tumor resistance to chemotherapy is a well-known clinical phenomenon that is yielding its secrets to investigation at the molecular level in biopsy material. Cell line studies and immunohistochemical studies of tumors suggest that resistance is a selective process: only those cells that survive a druginduced insult will re-grow. We have previously shown development of such resistance to combination chemotherapy in tumor-derived cells from matched biopsies collected from breast cancer patients before and after administration of doxorubicincontaining chemotherapy [2]. We have used real-time quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC) to assess targets known to be of importance to resistance to these agents
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