Antisense treatment against Ki-67 mRNA inhibits proliferation and tumor growth in vitro and in vivo.
The Ki-67 protein is tightly regulated and depends on the proliferative status of a cell. It is present in the nuclei of proliferating cells but absent in resting cells. Since transformation of malignant cells is frequently associated with high cell proliferation and since proliferation is tightly associated with the Ki-67 protein labeling index, this antigen may represent a potential target for cancer therapy. In the present study we determined the ability of a phosphorothioate antisense oligodeoxyribonucleotide (ODN) targeted against Ki-67 mRNA to inhibit tumor cell proliferation specifically in cell culture, in multicellular 3-dimensional spheroids (MCS) and in subcutaneous murine tumor models. Antisense treatment of 1 myeloid and different epithelial tumor cell lines in suspension and monolayer culture, respectively, resulted in specific reduction of Ki-67 mRNA and protein, inhibition of proliferation and increased apoptotic cell death. Multicellular human bladder carcinoma spheroids lost their 3-dimensional structure and underwent cell death after incubation with antisense oligonucleotides. The growth of subcutaneous syngeneic prostatic (p = 0.05) and transitional cell tumors (p = 0.001) in immunocompetent mice was significantly inhibited in antisense-treated animals. From these findings we conclude that antisense inhibition of Ki-67 protein expression may be a rational approach in anticancer therapy.
Department of Urology, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Ingo
I
Kausch
Anja
A
Lingnau
Elmar
E
Endl
Kirsten
K
Sellmann
Irina
I
Deinert
Timothy L
TL
Ratliff
Dieter
D
Jocham
Georg
G
Sczakiel
Johannes
J
Gerdes
Andreas
A
Böhle
D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000473:pathology / Q000628:therapy*; D018929:Cell Culture Techniques / Q000379:methods; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D015316:Genetic Therapy; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics*; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors*; D018874:Spheroids, Cellular / Q000187:drug effects; D013535:Suspensions; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000473:pathology / Q000628:therapy*
D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013535:Suspensions