Markers of drug resistance in relapsing colon cancer.
OBJECTIVE
5-Fluorouracil failure and drug resistance, which often occurs during chemotherapy, is still a great obstacle to the success of human colon cancer treatment. Thus, the comparative study of markers of drug resistance in cancer cells before and after chemotherapy may be extremely helpful in the selection of the appropriate chemotherapeutic drug in colon cancer patients who fail adjuvant treatment with 5-fluorouracil. In the present study we examined the differential expression of three multidrug resistance-related proteins (i.e., P-glycoprotein, MRP, and LRP) and of topoisomerase IIalpha in a series of 20 primary colon carcinomas and their recurrences.


METHODS
All markers were determined at tissue level by three-step immunohistochemistry using appropriate monoclonal antibodies, and the markers' immunopositivity was quantified by image analysis. In addition, Feulgen stain was used for the assessment of nuclear DNA content of malignant cells at their primary location.


RESULTS
Some degree of aneuploidy was detected in all primary carcinomas. The immunoexpression of the three multidrug resistance-related proteins did not change significantly, either qualitatively (positivity vs negativity) or quantitatively, after chemotherapy. On the contrary, the percentages of topoisomerase IIalpha-positive malignant cells were significantly increased in the tumour recurrences by comparison to their primary locations ( P=0.011).


CONCLUSIONS
According to our results, increased topoisomerase IIalpha immunohistochemical expression appears to be part of the malignant cells' phenotype in recurrent colon cancers. Therapeutic options after failure of 5-fluorouracil-based treatment could therefore include appropriate topoisomerase IIalpha-targeted drugs.
Lazaris
A C
AC
Department of Pathology, School of Medicine, The National and Capodistrian University of Athens, 75 Mikras Asias Street, Goudi, 115 27 Athens, Greece. alazaris@cc.uoa.gr
Kavantzas
N G
NG
Zorzos
H S
HS
Tsavaris
N V
NV
Davaris
P S
PS
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000782:Aneuploidy; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000096:biosynthesis*; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D010641:Phenotype; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis / Q000235:genetics; D000099187:Major Vault Protein
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005472:Fluorouracil; D009363:Neoplasm Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein