Cancer cell adaptation to chemotherapy

Federica Di Nicolantonio, Stuart J. Mercer, Louise A. Knight, Francis G. Gabriel, Pauline A. Whitehouse, Sanjay Sharma, Augusta Fernando, Sharon Glaysher, Silvana Di Palma, Penny Johnson, Shaw S. Somers, Simon Toh, Bernie Higgins, Alan Lamont, Tim Gulliford, Jeremy Hurren, Constantinos Yiangou, Ian A. Cree

Research output: Contribution to journalArticle

Abstract

Background: 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. 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. Methods: Cells 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. Results: In 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. Conclusion: This 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.

Original languageEnglish
Article number78
JournalBMC Cancer
Volume5
DOIs
Publication statusPublished - Jul 18 2005

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Drug Therapy
Neoplasms
Down-Regulation
Topotecan
Epirubicin
Type II DNA Topoisomerase
irinotecan
Biopsy
Fluorouracil
Doxorubicin
Cisplatin
Genes
Up-Regulation
Breast Neoplasms
Multiple Drug Resistance
Therapeutics
Paclitaxel
Pharmaceutical Preparations
Antineoplastic Agents
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Di Nicolantonio, F., Mercer, S. J., Knight, L. A., Gabriel, F. G., Whitehouse, P. A., Sharma, S., ... Cree, I. A. (2005). Cancer cell adaptation to chemotherapy. BMC Cancer, 5, [78]. https://doi.org/10.1186/1471-2407-5-78

Cancer cell adaptation to chemotherapy. / Di Nicolantonio, Federica; Mercer, Stuart J.; Knight, Louise A.; Gabriel, Francis G.; Whitehouse, Pauline A.; Sharma, Sanjay; Fernando, Augusta; Glaysher, Sharon; Di Palma, Silvana; Johnson, Penny; Somers, Shaw S.; Toh, Simon; Higgins, Bernie; Lamont, Alan; Gulliford, Tim; Hurren, Jeremy; Yiangou, Constantinos; Cree, Ian A.

In: BMC Cancer, Vol. 5, 78, 18.07.2005.

Research output: Contribution to journalArticle

Di Nicolantonio, F, Mercer, SJ, Knight, LA, Gabriel, FG, Whitehouse, PA, Sharma, S, Fernando, A, Glaysher, S, Di Palma, S, Johnson, P, Somers, SS, Toh, S, Higgins, B, Lamont, A, Gulliford, T, Hurren, J, Yiangou, C & Cree, IA 2005, 'Cancer cell adaptation to chemotherapy', BMC Cancer, vol. 5, 78. https://doi.org/10.1186/1471-2407-5-78
Di Nicolantonio F, Mercer SJ, Knight LA, Gabriel FG, Whitehouse PA, Sharma S et al. Cancer cell adaptation to chemotherapy. BMC Cancer. 2005 Jul 18;5. 78. https://doi.org/10.1186/1471-2407-5-78
Di Nicolantonio, Federica ; Mercer, Stuart J. ; Knight, Louise A. ; Gabriel, Francis G. ; Whitehouse, Pauline A. ; Sharma, Sanjay ; Fernando, Augusta ; Glaysher, Sharon ; Di Palma, Silvana ; Johnson, Penny ; Somers, Shaw S. ; Toh, Simon ; Higgins, Bernie ; Lamont, Alan ; Gulliford, Tim ; Hurren, Jeremy ; Yiangou, Constantinos ; Cree, Ian A. / Cancer cell adaptation to chemotherapy. In: BMC Cancer. 2005 ; Vol. 5.
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abstract = "Background: 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. 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. Methods: Cells 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. Results: In 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. Conclusion: This 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.",
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AU - Di Nicolantonio, Federica

AU - Mercer, Stuart J.

AU - Knight, Louise A.

AU - Gabriel, Francis G.

AU - Whitehouse, Pauline A.

AU - Sharma, Sanjay

AU - Fernando, Augusta

AU - Glaysher, Sharon

AU - Di Palma, Silvana

AU - Johnson, Penny

AU - Somers, Shaw S.

AU - Toh, Simon

AU - Higgins, Bernie

AU - Lamont, Alan

AU - Gulliford, Tim

AU - Hurren, Jeremy

AU - Yiangou, Constantinos

AU - Cree, Ian A.

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N2 - Background: 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. 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. Methods: Cells 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. Results: In 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. Conclusion: This 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.

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