mdm2-p53 Interaction: lack of correlation with the response to 5-fluorouracil in advanced colorectal cancer.
OBJECTIVE
We investigated the relevance of mdm2 and p53 primary tumour expression to the clinical outcome of a consecutive series of advanced colorectal cancer patients treated with a 5-fluorouracil-based chemotherapy.


METHODS
The expression of p53 and mdm2 was analyzed by an immunohistochemical assay in 80 formalin-fixed paraffin embedded primary tumour samples and related to the clinical response to 5-fluorouracil therapy and to the prognosis of the patients. In a subgroup of 46 tumours, the apoptotic index (AI) as determined by the Tunel technique was also assessed.


RESULTS
Nuclear immunostaining of p53 and mdm2 was present in 42 and 30% of the cases, respectively. No correlation was demonstrated between p53 and mdm2 expression (rs = -0.01; p > 0.05). With regard to the clinical outcome, no statistical association was demonstrated among p53 and mdm2 expression, AI, probability of clinical response to treatment, time to progression, or overall survival. The subgroup of patients with a p53-negative/mdm2-positive tumour showed a worse response rate (15%); however, mdm2-positive/AI-negative tumours showed a 0% (0/7) probability of a clinical response as compared with 30% (9/30) of the remaining tumour patient subgroups; this also translated in a significantly worse overall survival probability (p = 0.01 by log rank).


CONCLUSIONS
The analysis of mdm2 expression does not add significant clinical information in colorectal cancers with a different p53 status. Conversely, further analysis of AI seems to give data of a promising prognostic-predictive value.
Paradiso
A
A
Clinical Experimental Oncology Laboratory, Oncology Institute, Bari, Italy. anpara@tin.it
Ranieri
G
G
Simone
G
G
Silvestris
N
N
Costa
A
A
De Lena
M
M
Leone
A
A
Vallejo
C
C
Lacava
J
J
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D015996:Survival Rate; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005472:Fluorouracil