Radioimmunotherapy and apoptotic induction on CK19-overexpressing human cervical carcinoma cells with Re-188-mAbCx-99.
BACKGROUND
The overexpression of Ck19 antigen occurs frequently in human carcinomas. The strategy and mechanism of radioimmunotherapy using Re-188-mAbCx-99 to Ck19 on human cervical carcinoma cells was investigated in this study.


METHODS
Using mAbCx-99, the overexpression of Ck19 protein in lysates of cell lines and tissues from various patients' cervixes were verified by immunobinding and immunoblot analysis. The therapeutic effect of Re-188-mAbCx-99 on ME180 cells was examined in vitro by cell proliferation, apoptosis, DNA fragmentation and intemucleosomal levels.


RESULTS
A relatively high expression of Ck19 was found in all human cervical carcinoma cell lines (4- to 44-fold) and in tissue lysates (26.8- to 79-fold) from patients (31 out of 34) with cervical, endometrial or ovarian carcinomas compared with that of benign or normal control samples. The growth inhibition of ME180, CC7T and Hela cells were significantly higher (p < 0.001) in the Re-188-mAbCx-99-treated (60-80%) than in the Re-188-MOPCIgG1-treated lines (8-18%) after 72-h treatment. After 48 h of treatment with Re-188-mAbCx-99, ME180 cells significantly exhibited DNA fragmentation and morphological features of apoptosis. This effect markedly elevated the expression of p21, p53 and Bcl-xS protein, while the Mcl-1 and Caspase-8 proteins were down-regulated.


CONCLUSIONS
We suggest that an elevated Ck19 level is associated with disease stage in most patients with cervical cancer. The therapeutic effect of Re-188-mAbCx-99 was verified through apoptosis on targeting the enriched Ck19 protein of carcinoma cells.
Chang
Chih-Hsien
CH
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
Tsai
Lai-Chen
LC
Chen
Shui-Tein
ST
Yuan
Chiou-Chung
CC
Hung
Mei-Whey
MW
Hsieh
Bor-Tsung
BT
Chao
Pei-Ling
PL
Tsai
Tung-Hu
TH
Lee
Te-Wei
TW
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000918:Antibody Specificity; D017209:Apoptosis / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000528:radiation effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007633:Keratins / Q000096:biosynthesis* / Q000276:immunology; D009707:Nucleosomes / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000494:pharmacology*; D012211:Rhenium / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*
D000911:Antibodies, Monoclonal; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000922:Immunotoxins; D009707:Nucleosomes; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D011868:Radioisotopes; D016159:Tumor Suppressor Protein p53; D007633:Keratins; D012211:Rhenium