[Ki-67 antisense therapy in murine renal cell carcinoma models].
OBJECTIVE
The Ki-67 antigen is only expressed in proliferating cells. Previously, it was shown that Ki-67 derived antisense oligonucleotides (asONs) specifically inhibit the proliferation of tumor cells and tumour growth in vitro and in subcutaneous bladder and prostate tumor models. We intended to evaluate the effects of this therapeutic concept in two renal cell carcinoma (RCC) models.


METHODS
Human RCC cells (SK-RC 35) were initially transfected with FITC-labeled ONs and diffferent cationic lipids to analyze the transfection efficacy by flow cytometry (FACS). The potency of 14 different ONs sequences was compared by quantitative RT-PCR in vitro. For in vivo testing, ONs were administered to immunocompetent Balb/c mice bearing orthotopic RENCA tumors as well as to SCID mice bearing subcutaneous RCC SK-RC 35 xenografts. Tumor sizes and final tumor weights were documented. Additionally, several immunohistochemical staining procedures were performed.


RESULTS
FACS analysis showed highly effective transfection conditions in vitro. Systemic administration of asONs significantly decreased the tumour growth in the RENCA model (p < 0.05) and in the SCID mouse model (p = 0.009). Immunohistochemical staining of tumor specimens revealed a marked down-regulation of target protein and a slight increase in apoptotic cells after antisense treatment while the microvessel count was not significantly altered.


CONCLUSIONS
These results demonstrate that the Ki-67 antigen represents a suitable antiproliferative target and that asONs directed against this target are potent drugs that induce a significant inhibition of renal tumor growth in different mouse models.
Kausch
I
I
Klinik und Poliklinik für Urologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck.
Jiang
H
H
Brocks
C
C
Albers
A
A
Krüger
S
S
Sczakiel
G
G
Jocham
D
D
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics*; D007680:Kidney Neoplasms / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D014162:Transfection
D019394:Ki-67 Antigen; D016376:Oligonucleotides, Antisense