Sequential X-irradiation induced acquired resistance to oxaliplatin but increased sensitivity to cisplatin in two human teratoma cell lines in vitro.
Cisplatin (CDDP) and oxaliplatin (OXA-P) are potential therapeutic drugs in the treatment of testicular cancer. However, the emergence of drug resistance has been documented not only in patients after chemotherapy but also subsequently to fractionated X-irradiation. Specific radiation-induced biochemical alterations may play a role in the observed resistance. Since irradiation influences the cellular responses to chemotherapy, this study investigated changes in the expression of key proteins in the regulation of DNA repair and apoptosis subsequent to sequential irradiation.


METHODS
Logarithmically growing human teratocarcinoma cell lines 2101 EP and H 12.1 were irradiated (10 fractions of 4 Gy in vitro) to establish the sub-lines 2101 EP/DXR-10 and H 12.1/DXR-10. Radiosensitivity was assayed using a clonogenic survival assay. Drug response was assayed using a sulforhodamine B assay. Expression of p53, PARP, hMSH2 and Fas was detected by Western blotting.


RESULTS
Both DXR-10 sub-lines showed a significant increase in sensitivity towards CDDP as compared to their parental cell line, however, there was a concomitant increase in resistance against OXA-P. No significant changes in radiosensitivity between parental and DXR-10 cell lines were observed. In addition, there was an up-regulation of PARP, p53, hMSH2 and Fas in the DXR-10 sub-lines, implicating induced damage tolerance and repair mechanisms following irradiation.


CONCLUSIONS
These results suggest that radiation preceding chemotherapy might induce resistance to subsequent chemotherapy with oxaliplatin but not to cisplatin. This is a novel observation and, if confirmed, particularly in other tumor types, may have clinical implications.
Department of Medical Oncology and Haematology, Martin Luther University, D-06120 Halle/Saale, Germany.
Stephan
S
Eisenmann
Wieland
W
Voigt
Thomas
T
Müller
Wolfram
W
Dempke
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D018243:Teratocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays; D019014:fas Receptor / Q000378:metabolism
D000970:Antineoplastic Agents; C491901:FAS protein, human; D009944:Organoplatinum Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D000077150:Oxaliplatin; D011065:Poly(ADP-ribose) Polymerases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D002945:Cisplatin