Cancer cell adaptation to chemotherapy.
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 IIalpha (TOPOIIalpha). Exposure to topotecan in vitro, resulted in >4-fold down-regulation of TOPOIIalpha in 6/7 colorectal tumors and 8/10 ovarian tumors.


CONCLUSIONS
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.
Di Nicolantonio
Federica
F
Translational Oncology Research Centre, Department of Histopathology, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK. federicadn@hotmail.com
Mercer
Stuart J
SJ
Knight
Louise A
LA
Gabriel
Francis G
FG
Whitehouse
Pauline A
PA
Sharma
Sanjay
S
Fernando
Augusta
A
Glaysher
Sharon
S
Di Palma
Silvana
S
Johnson
Penny
P
Somers
Shaw S
SS
Toh
Simon
S
Higgins
Bernie
B
Lamont
Alan
A
Gulliford
Tim
T
Hurren
Jeremy
J
Yiangou
Constantinos
C
Cree
Ian A
IA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001706:Biopsy; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004358:Drug Therapy / Q000379:methods*; D015251:Epirubicin / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019772:Topotecan / Q000494:pharmacology; D016896:Treatment Outcome; D015854:Up-Regulation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D015251:Epirubicin; D000077146:Irinotecan; D019772:Topotecan; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil; D002166:Camptothecin