The relative activity of cisplatin, oxaliplatin and satraplatin in testicular germ cell tumour sensitive and resistant cell lines.
BACKGROUND
Germ cell tumours (GCT) can become resistant to cisplatin, which is associated with a relatively poor prognosis. Oxaliplatin and satraplatin have been developed to overcome cisplatin resistance in other cancers, but their effect in cisplatin resistant (cisR) GCTs is unclear. In this work we address this issue by comparing their efficacy in three paired sensitive and cisR GCT cell lines.


METHODS
Three established cisplatin sensitive (cisS) and resistant cell line pairs were used (GCT27, GCT27r: SUSA, SUSAr: 833k, 833kr). Viability was assessed using a luciferase based ATP assay and EC(50) and EC(80) concentrations were calculated. Western blot analysis and flow cytometry was used for further assessment.


RESULTS
Sensitivity to the three platinum compounds was broadly similar in the three cisS lines GCT cell lines (EC(50) = 0.27-0.51 microM for cisplatin, 0.52-0.79 microM for oxaliplatin, 0.31-1.26 microM for satraplatin). EC(50) values for cisplatin in the three cisR sub lines were 1.8- to 3.8-fold higher than in the sensitive parental lines. Cross resistance to satraplatin and oxaliplatin occurred in all three cisR cell lines (resistance factor 1.9-4.4), with the exception of oxaliplatin in the 833Kr (resistance factor 0.9). Differences in the effect of specific drugs on cell cycle distribution, p53, p21 and MDM2 were observed.


CONCLUSIONS
These data suggest that satraplatin and oxaliplatin could theoretically be used in chemo-naive GCTs and support the further clinical evaluation of these agents in this setting. The mechanism of cross resistance to these drugs appears multifactorial.
Perry
Jackie
J
Orchid Cancer Pharmacology Group, Centre for Experimental Cancer Medicine, Institute of Cancer, St Bartholomew's Hospital, West Smithfield, London, UK.
Powles
Thomas
T
Shamash
Jonathan
J
Veerupillai
Arthi
A
McGrowder
Eva
E
Noel
Elodie
E
Lu
Yong-Jie
YJ
Oliver
Tim
T
Joel
Simon
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; C081294:satraplatin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D015689:Oncogene Protein p21(ras); D002945:Cisplatin