Quantitation of the change in GADD153 messenger RNA level as a molecular marker of tumor response in head and neck cancer.
Cells injured by exposure to cisplatin (cDDP) undergo a cellular injury response that shares characteristics with responses produced by many other injurious agents. We sought to determine whether the increase of the message of the "growth arrest and DNA damage-inducible" gene, GADD153, could be used to assess the extent of the cellular injury response in model systems and in patients with head and neck cancer after treatment with cDDP. The mRNA levels of GADD153, a gene highly transcriptionally activated by cDDP damage, were increased in a transient, concentration-dependent manner by cDDP when human UMSCC10b head and neck carcinoma cells were treated with cDDP both in vitro and when grown as tumor xenografts in nude mice. There was a good correlation between the change in level of GADD153 mRNA and UMSCC10b cell kill by cDDP in vitro (r = 0.98). The magnitude of the increase was proportionally reduced in UMSCC10b sublines that were 3- or 6-fold resistant to cDDP. GADD153 mRNA levels were measured in biopsies obtained before and 24 h after treatment with cDDP from 32 patients with stage III/IV head and neck cancer. There was a relationship between the increase in GADD153 mRNA levels and the response rate. Seven of the 32 patients had no response and no increase in GADD153 mRNA level. Among the eight patients who attained a partial response, the increase in GADD153 message ranged from 0.7-2.5-fold. In contrast, 17 of 32 patients had a complete response, and this was accompanied by a 2-9-fold induction of GADD153. The mean increase in the complete responders (3.8+/-2.2-fold) differed significantly from that for the partial responders (1.6+/-0.9) and nonresponders (0.8+/-0.5; P <0.05); the difference between the partial responders and nonresponders was also significant (P <0.05). An increase of GADD153 mRNA of 1.75-fold or higher predicted a complete response, with a sensitivity of 94% and a specificity of 87%. We conclude that the magnitude of the increase in GADD153 mRNA is a promising candidate for service as an intermediate marker of head and neck tumor response to cDDP. The fact that the change in GADD153 mRNA reflects the actual extent of injury sustained by the tumor makes it particularly attractive as a potential marker. One strength of this approach is that it can provide a measure of the effectiveness of therapy as early as 24-48 h after the first dose of treatment.
Los
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UCSD Cancer Center, University of California, San Diego, La Jolla 92093-0058, USA.
Benbatoul
K
K
Gately
D P
DP
Barton
R
R
Christen
R
R
Robbins
K T
KT
Vicario
D
D
Kirmani
S
S
Orloff
L A
LA
Weisman
R
R
Howell
S B
SB
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; D002945:Cisplatin / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017063:Outcome Assessment, Health Care / Q000379:methods; D016133:Polymerase Chain Reaction; D011786:Quality Control; D012333:RNA, Messenger / Q000378:metabolism; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D002945:Cisplatin