Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma

被引:82
作者
Gorlick, R
Metzger, R
Danenberg, KD
Salonga, D
Miles, JS
Longo, GSA
Fu, J
Banerjee, D
Klimstra, D
Jhanwar, S
Danenberg, PV
Kemeny, N
Bertino, JR
机构
[1] Mem Sloan Kettering Canc Ctr, Dept Pediat, Program Mol Pharmacol & Therapeut, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
[3] Mem Sloan Kettering Canc Ctr, Dept Human Genet, New York, NY 10021 USA
[4] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA
[5] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol, New York, NY 10021 USA
[6] Mem Sloan Kettering Canc Ctr, Dept Expt Therapeut, New York, NY 10021 USA
[7] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA
关键词
D O I
10.1200/JCO.1998.16.4.1465
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: It has been observed previously that the pulmonary metastases of colorectal adenocarcinoma are less responsive to therapy with fluorouracil (FUra) as compared with other sites of metastasis (liver, local). To investigate the basis of this chemoresistance, the levels of thymidylate synthase (TS) mRNA and protein were measured, as TS expression has been shown to be predictive of response to therapy in colorectal cancer. Materials and Methods: Tumors were obtained from 19 patients with metastatic colorectal cancer(12 hepatic and seven pulmonary). TS expression was measured by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and TS protein levels were measured by Western blotting. The presence of TS amplification was assessed by Southern blotting. Levels of p53 protein were determined using immunohistochemistry. Results: TS mRNA expression was shown to be significantly higher in the pulmonary metastases (mean TS/beta-actin ratio, 19.7; n = 7) as compared with the hepatic metastases (mean TS/beta-actin ratio, 4.7; n = 11) of colorectal cancer. Lower TS expression was observed in patients with hepatic metastases who had received prior FUra versus patients who had not been treated. High levels of TS expression in some samples was associated with low-level (two to three gene copies) increases in TS gene copy numbers and this was observed more frequently in the pulmonary metastatic samples. The increased gene copy numbers occurred both in samples with wild-type p53 and those with mutant p53 tumor-suppressor gene as determined by immunohistochemistry. Conclusion: High levels of TS enzyme may be the basis of the lack of response of pulmonary metastases to FUra treatment. (C) 1998 by American Society of Clinical Oncology.
引用
收藏
页码:1465 / 1469
页数:5
相关论文
共 24 条
[1]   EVALUATION OF 6 ANTIBODIES FOR IMMUNOHISTOCHEMISTRY OF MUTANT P53 GENE-PRODUCT IN ARCHIVAL COLORECTAL NEOPLASMS [J].
BAAS, IO ;
MULDER, JWR ;
OFFERHAUS, GJA ;
VOGELSTEIN, B ;
HAMILTON, SR .
JOURNAL OF PATHOLOGY, 1994, 172 (01) :5-12
[2]   p53 nuclear protein overexpression in colorectal cancer: A dominant predictor of survival in patients with advanced hepatic metastases [J].
Belluco, C ;
Guillem, JG ;
Kemeny, N ;
Huang, Y ;
Klimstra, D ;
Berger, MF ;
Cohen, AM .
JOURNAL OF CLINICAL ONCOLOGY, 1996, 14 (10) :2696-2701
[3]   CANCER STATISTICS, 1993 [J].
BORING, CC ;
SQUIRES, TS ;
TONG, T .
CA-A CANCER JOURNAL FOR CLINICIANS, 1993, 43 (01) :7-26
[4]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[5]  
DEGREGORI J, 1995, MOL CELL BIOL, V15, P4215
[6]   Functional roles of E2F in cell cycle regulation [J].
Fan, JG ;
Bertino, JR .
ONCOGENE, 1997, 14 (10) :1191-1200
[7]   Surgery for lung metastases from colorectal cancer: Analysis of prognostic factors [J].
Girard, P ;
Ducreux, M ;
Baldeyrou, P ;
Rougier, P ;
LeChevalier, T ;
Bougaran, J ;
Lasser, P ;
Gayet, B ;
Ruffie, P ;
Grunenwald, D .
JOURNAL OF CLINICAL ONCOLOGY, 1996, 14 (07) :2047-2053
[8]   AMPLIFICATION OF THE DIHYDROFOLATE-REDUCTASE GENE IS A MECHANISM OF ACQUIRED-RESISTANCE TO METHOTREXATE IN PATIENTS WITH ACUTE LYMPHOBLASTIC-LEUKEMIA AND IS CORRELATED WITH P53 GENE-MUTATIONS [J].
GOKER, E ;
WALTHAM, M ;
KHERADPOUR, A ;
TRIPPETT, T ;
MAZUMDAR, M ;
ELISSEYEFF, Y ;
SCHNIEDERS, B ;
STEINHERZ, P ;
TAN, C ;
BERMAN, E ;
BERTINO, JR .
BLOOD, 1995, 86 (02) :677-684
[9]  
HORIKOSHI T, 1992, CANCER RES, V52, P108
[10]  
HUGHES K, 1989, SURG CLIN N AM, V69, P340