Induction of the growth arrest and DNA damage-inducible gene GADD153 by cisplatin in vitro and in vivo.
The inability to assess the extent of tumour damage immediately following treatment is a major clinical obstacle to improving the management of cancer patients. Normally, the effectiveness of chemotherapy or radiation therapy cannot be determined for at least several weeks after treatment. We studied the increase in mRNA of the growth arrest and DNA damage-inducible gene GADD153 in human 2008 ovarian carcinoma cells in vitro and in vivo to determine whether treatment-induced increases in the level of GADD153 mRNA could be used as a marker of the extent of tumour damage. GADD153 mRNA was increased in a transient, dose-dependent manner by cisplatin (DDP) when the tumour cells were grown both in vitro and as tumour xenografts in nude mice. The magnitude of induction of GADD153 mRNA did not vary significantly between different 2008 xenografts treated with equal doses of DDP, and GADD153 mRNA induction correlated with the degree of in vitro cytotoxicity for two different schedules of drug exposure. DDP increased GADD153 mRNA levels in melanoma and head and neck xenograft models as well. We conclude that the increase in GADD153 mRNA can be used to detect tumour injury at time points as short as 24 h after administration of DDP.
Gately
D P
DP
Department of Biomedical Sciences, University of California, San Diego, La Jolla.
Jones
J A
JA
Christen
R
R
Barton
R M
RM
Los
G
G
Howell
S B
SB
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000235:genetics*; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D013997:Time Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D002945:Cisplatin