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Reduced drug accumulation is more important in acquired resistance against oxaliplatin than against cisplatin in isogenic colon cancer cells.

Ekblad, Lars LU ; Kjellström, Johan LU and Johnsson, Anders LU (2010) In Anti-Cancer Drugs 21. p.523-531
Abstract
Preclinical studies have indicated that there is only partial cross-resistance between cisplatin and oxaliplatin. The molecular background for this is incompletely known. To investigate the differences in resistance, we rendered a colon cancer cell line (S1) resistant against cisplatin and oxaliplatin and characterized the subclones with regard to cross-resistance, platinum uptake, and gene expression profiles. Four oxaliplatin and four cisplatin-resistant cell lines were produced from S1 by step-wise increasing the concentrations of the drugs in the growth medium. Cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and platinum accumulation in cell lysates and DNA preparations by... (More)
Preclinical studies have indicated that there is only partial cross-resistance between cisplatin and oxaliplatin. The molecular background for this is incompletely known. To investigate the differences in resistance, we rendered a colon cancer cell line (S1) resistant against cisplatin and oxaliplatin and characterized the subclones with regard to cross-resistance, platinum uptake, and gene expression profiles. Four oxaliplatin and four cisplatin-resistant cell lines were produced from S1 by step-wise increasing the concentrations of the drugs in the growth medium. Cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and platinum accumulation in cell lysates and DNA preparations by inductively coupled plasma mass spectroscopy. Gene expression was investigated by cDNA microarrays. The protein expression of the ATP-binding cassette B1 (ABCB1) was measured by immunohistochemistry. The cisplatin-resistant cell lines were 1.5-6.2-fold resistant against cisplatin and the oxaliplatin-resistant sublines 2.6-17-fold resistant against oxaliplatin. There was a limited degree of cross-resistance. Oxaliplatin resistance could be explained to a larger degree by reduced drug accumulation whereas mechanisms for increased tolerance against platinum incorporation in DNA seemed to be of higher importance for resistance against cisplatin. A greater number of ABC transporters were upregulated in the oxaliplatin-resistant cell lines compared with those selected for cisplatin resistance. ABCB1 was highly overexpressed in the three most oxaliplatin-resistant sublines, but significantly underexpressed in the two most cisplatin-resistant cell lines. This was also confirmed by immunohistochemistry. However, functional tests did not show any increase in ABCB1 transport activity in the oxaliplatin-resistant sub-lines compared with S1. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Anti-Cancer Drugs
volume
21
pages
523 - 531
publisher
Rapid Communications
external identifiers
  • wos:000277308100007
  • pmid:20168208
  • scopus:77951261957
ISSN
0959-4973
DOI
10.1097/CAD.0b013e328337b867
language
English
LU publication?
yes
id
0b36da22-91b9-4e96-89f3-1530304f556c (old id 1552503)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20168208?dopt=Abstract
date added to LUP
2010-03-03 13:48:22
date last changed
2018-06-10 04:50:19
@article{0b36da22-91b9-4e96-89f3-1530304f556c,
  abstract     = {Preclinical studies have indicated that there is only partial cross-resistance between cisplatin and oxaliplatin. The molecular background for this is incompletely known. To investigate the differences in resistance, we rendered a colon cancer cell line (S1) resistant against cisplatin and oxaliplatin and characterized the subclones with regard to cross-resistance, platinum uptake, and gene expression profiles. Four oxaliplatin and four cisplatin-resistant cell lines were produced from S1 by step-wise increasing the concentrations of the drugs in the growth medium. Cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and platinum accumulation in cell lysates and DNA preparations by inductively coupled plasma mass spectroscopy. Gene expression was investigated by cDNA microarrays. The protein expression of the ATP-binding cassette B1 (ABCB1) was measured by immunohistochemistry. The cisplatin-resistant cell lines were 1.5-6.2-fold resistant against cisplatin and the oxaliplatin-resistant sublines 2.6-17-fold resistant against oxaliplatin. There was a limited degree of cross-resistance. Oxaliplatin resistance could be explained to a larger degree by reduced drug accumulation whereas mechanisms for increased tolerance against platinum incorporation in DNA seemed to be of higher importance for resistance against cisplatin. A greater number of ABC transporters were upregulated in the oxaliplatin-resistant cell lines compared with those selected for cisplatin resistance. ABCB1 was highly overexpressed in the three most oxaliplatin-resistant sublines, but significantly underexpressed in the two most cisplatin-resistant cell lines. This was also confirmed by immunohistochemistry. However, functional tests did not show any increase in ABCB1 transport activity in the oxaliplatin-resistant sub-lines compared with S1.},
  author       = {Ekblad, Lars and Kjellström, Johan and Johnsson, Anders},
  issn         = {0959-4973},
  language     = {eng},
  pages        = {523--531},
  publisher    = {Rapid Communications},
  series       = {Anti-Cancer Drugs},
  title        = {Reduced drug accumulation is more important in acquired resistance against oxaliplatin than against cisplatin in isogenic colon cancer cells.},
  url          = {http://dx.doi.org/10.1097/CAD.0b013e328337b867},
  volume       = {21},
  year         = {2010},
}