Abstract
Background. Cell cycle arrest after DNA damage is partly mediated through the transcriptional
activation of p21WAF1 by the p53 tumor suppressor gene. p21WAF1 and p53 are both critical in maintaining cell cycle control in response to DNA damage
from radiation or chemotherapy. Therefore, we examined the role of p21WAF1 and p53 in the determination of outcome for patients who receive radiation and/or
chemotherapy for pancreatic cancer. Methods. p21WAF1 and p53 protein expression were determined (with the use of immunohistochemistry)
in specimens from 90 patients with pancreatic cancer. Forty-four patients underwent
surgical resection, and 46 patients had either locally unresectable tumors (n = 9
patients) or distant metastases (n = 37 patients). Seventy-three percent of the patients
who underwent resection and 63% of the patients who did not undergo resection received
radiation and/or chemotherapy. Results. p21WAF1 expression was present in 48 of 86 tumors (56%) and was significantly (P <.05) associated with advanced tumor stage. Median survival among patients with resected
pancreatic cancer who received adjuvant chemoradiation with p21WAF1-positive tumors was significantly longer than in patients with no p21WAF1 staining (25 vs 11 months; P =.01). Fifty of 89 tumors (56%) stained positive for p53 protein. p53 overexpression
was associated with decreased survival in patients who did not undergo resection.
Conclusions. Normal p21WAF1 expression may be necessary for a beneficial response to current adjuvant chemoradiation
protocols for pancreatic cancer. Alternate strategies for adjuvant therapy should
be explored for patients with pancreatic cancer who lack functional p21WAF1. (Surgery 2000;128:520-30.)
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to SurgeryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer statistics, 1999.CA Cancer J Clin. 1999; 49: 8-31
- Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival.Ann Surg. 1997; 225: 621-636
- Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region.Ann Surg. 1999; 230: 776-784
- Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer.Cancer. 1987; 59: 2006-2010
- Molecular pathology of primary and metastatic ductal pancreatic lesions.Cancer. 1997; 79: 700-716
- Disruption of p53 in human cancer cells alters the responses to therapeutic agents.J Clin Invest. 1999; 104: 263-269
- Requirement for p53 and p21 to sustain G2 arrest after DNA damage.Science. 1998; 282: 1497-1501
- p21 is necessary for the p53-mediated G 1 arrest in human cancer cells.Cancer Res. 1995; 55: 5187-5190
- p53 mutation and locoregional treatment failure in head and neck squamous cell carcinoma.J Natl Cancer Inst. 1996; 88: 1580-1586
- Loss of normal p53 function confers sensitization to taxol by increasing G2/M arrest and apoptosis.Nature Med. 1996; 2: 72-79
- 5th ed. American Joint Committee on cancer: exocrine pancreas: AJCC cancer staging manual. Lippincott-Raven, Philadelphia1997: 121-126
- Clinical implications of the p53 gene.Annu Rev Med. 1996; 47: 285-301
- Cell cycle control and cancer.Science. 1994; 266: 1821-1828
- WAF1, a potential mediator of p53 tumor suppression.Cell. 1993; 75: 817-825
- Absence of WAF1 mutations in a variety of human malignancies.Blood. 1994; 84: 3781-3784
- Induction of p21WAF1 expression and growth inhi-bition by transforming growth factor β involve the tumor suppressor gene DPC4 in human pancreatic adenocarcinoma cells.Cancer Res. 1997; 57: 3929-3934
- DPC4 a candidate tumor suppressor gene at human chromosome 18q21.1.Science. 1996; 271: 350-353
- Comparative significance of p53 and WAF/1-p21 expression on the efficacy of adjuvant chemotherapy for resectable invasive ductal carcinoma of the pancreas.Pancreas. 1999; 18: 117-126
- Nuclear accumulation of p53 correlates significantly with clinical features and inversely with expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in pancreatic cancer.Br J Cancer. 1997; 76: 299-305
- Analysis of p53, p21WAF1, and TGF-β1 in human ductal adenocarcinoma of the pancreas.Am J Clin Pathol. 1998; 110: 16-23
- The clinical significance of p21WAF1/CIP-1 and p53 expression in pancreatic adenocarcinoma.Cancer. 1997; 80: 372-381
- Overexpression of p53 protein in adenocarcinoma of the pancreas.Am J Clin Path. 1994; 101: 684-688
- p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma.Am J Pathol. 1995; 147: 884-888
- Molecular metastases in stage I pancreatic cancer: improved survival with adjuvant chemoradiation.Surgery. 1998; 124: 663-669
Article info
Footnotes
*Reprint requests: Michael J. Demeure, MD, Department of Surgery, The Medical College of Wisconsin, 9200 West Wisconsin Ave, Milwaukee, WI 53226.
**Surgery 2000;128:520-30
Identification
Copyright
© 2000 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
