p53 status correlates with histopathological response in patients with soft tissue sarcomas treated using isolated limb perfusion with TNF-alpha and melphalan.
BACKGROUND
Recombinant tumor necrosis factor-alpha (TNF-alpha) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-alpha and loss of p53 function contributes to the resistance of tumour cells to TNF-alpha. The relationship between p53 status and response to TNF-alpha and melphalan in patients undergoing ILP is unknown.


METHODS
We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters.


RESULTS
P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-alpha and melphalan showed significantly higher levels of p53-mutated protein.


CONCLUSIONS
Our results might be a clue to a role of p53 protein status in TNF-alpha and melphalan response in clinical use.
Department of AnesthesiaInstitut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. muret@igr.fr
J
J
Muret
M
M
Yacoub
P
P
Terrier
F
F
Drusch
A
A
Laplanche
C
C
Gaudin
C
C
Richon
C
C
Le Péchoux
A
A
Le Cesne
F J
FJ
Lejeune
T
T
Tursz
P
P
Fouret
S
S
Bonvalot
S
S
Chouaib
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology; D010478:Chemotherapy, Cancer, Regional Perfusion; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D020125:Mutation, Missense; D012509:Sarcoma / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000235:genetics / Q000276:immunology
D014408:Biomarkers, Tumor; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D008558:Melphalan