Release: July 29, 2000
Contact: Kenneth Satterfield
703-519-1563
[email protected]
In San Francisco (7/28-8/2)
415-284-8082
AN ASSOCIATION BETWEEN THE p53 GENE MUTATION IN HEAD AND NECK CANCERS AND CHEMOSENSITIVITY IS ESTABLISHED
San Francisco, CA: One of the critical factors for successful organ preservation is selecting the tumors that respond to chemotherapy and radiotherapy. However, both treatments are limited by the inability to predict which patients are likely to respond. To accomplish successful organ sparing and allow prompt surgical treatment of those patients for whom chemotherapy and radiotherapy is unlikely to work, it is necessary to identify those patients most likely to respond.
Mutation of the p53 gene is present in 40-60 percent of head and neck cancers. The p53 gene product is important in cell cycle regulation, DNA repair and apoptosis. Previous experiments indicated that head and neck tumors that overexpressed p53 were more sensitive to chemotherapy with cisplatin and 5-fluorouracil.
Now, a team of head and neck surgeons from the University of Michigan have completed a study that reveals most of the head and neck squamous cell carcinoma (HNSCC) tumor cell lines with p53 mutations are sensitive to cisplatin whereas those with wild-type p53 tend to be more resistant.
The authors of the study, "Correlation of p53 Mutation and Chemosensitivity in Head and Neck Squamous Cell Carcinoma Lines," are Shaobo Zhu MD, Haruko Ogawa MD, Tetsuya Ogawa MD, Thomas E. Carey MD, Gregory T. Wolf MD, and Carol R. Bradford MD, all from the Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan. The work was supported by grants from the National Cancer Institute, the National Institute for Dental and Craniofacial Research, and the 1997 Percy Memorial Research Award. Their findings were presented before the 5th International Conference on Head and Neck Cancer, being held July 29 through August 2, at the San Francisco Marriott, San Francisco, CA. More than 1,500 leading head and neck surgeons from the United States and 46 nations will gather to hear the latest medical research in the diagnosis, treatment, and reconstruction associated with head and neck cancer. The medical conference is sponsored by the American Head and Neck Society, www.headandneckcancer.org.
Methodology: To determine the relationship of p53 mutations to chemosensitivity, 23 head and neck squamous cell carcinoma (HNSCC) cell lines were analyzed for in vitro cisplatin sensitivity, for p53 expression, and for p53 mutation in exons 4 through 10. Abnormalities of the p53 gene were screened for using single strand conformational polymorphism (SSCP) analysis of each exon. All cell lines with abnormal bands also had p53 mutation determined by DNA sequencing. Sensitivity to cisplatin for all 23 cell lines were was tested by the MTT assay.
Results: Abnormal p53 bands were detected by SSCP analysis in 13/23 (56.5 percent) cell lines. Ten of these mutations were point mutations, two mutations resulted in a stop codon, and one mutation resulted in a two-codon deletion. p53 protein over expression was found in 11/13 (84.6 percent) cell lines with p53 mutations by Western Blot.
One of the two cell lines with mutant p53 that does not over express the p53 protein has an early termination codon and the other has a two-codon deletion. The cell line with a stop codon in exon 8 does over express a truncated p53 protein. Those cell lines with wild-type p53 had little or no expression of p53 protein. Nine of 13 cell lines with p53 mutation were highly sensitive to cisplatin (ID less than 5uM) and 6/10 cell lines with wildtype p53 were very resistant (ID50 greater than 10uM). The average ID50 (drug dose required to inhibit 50 percent of cell growth) for all p53 mutants was 6.6 uM, while the average ID50 for cell lines with wildtype p53 was 14.9 uM (p less than 0.02, student's t-test).
Conclusion: p53 mutation and over expression predict chemotherapy response in head and neck cancer. Now, identification of these predictors and their response to specific chemotherapy will assist in determining what treatment will provide the optimum response.
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