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[Ki-67 antisense therapy in murine renal cell carcinoma models]
1Klinik und Poliklinik für Urologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck.
Purpose:
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.
Material And 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.
Conclusion:
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.
Insights
Antisense oligonucleotides targeting the Ki-67 antigen effectively inhibited renal tumor growth in mouse models. This study validates Ki-67 as a therapeutic target for renal cell carcinoma (RCC) treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Context:
- The Ki-67 antigen is a biomarker for cellular proliferation.
- Antisense oligonucleotides (asONs) targeting Ki-67 have shown promise in inhibiting tumor growth in preclinical models.
- Renal cell carcinoma (RCC) remains a significant health concern, necessitating novel therapeutic strategies.
Purpose:
- To evaluate the efficacy of Ki-67-targeting asONs in two distinct renal cell carcinoma (RCC) mouse models.
- To assess the antiproliferative and tumor-inhibitory effects of asONs in vivo.
- To validate Ki-67 as a viable therapeutic target for RCC.
Summary:
- Systemic administration of Ki-67 asONs significantly reduced tumor growth in both orthotopic RENCA and subcutaneous SK-RC 35 RCC mouse models.
- In vitro studies confirmed effective transfection conditions and identified potent asON sequences.
- Immunohistochemical analysis revealed target protein downregulation and increased apoptosis in treated tumors, without significant changes in microvessel density.
Impact:
- Demonstrates the therapeutic potential of Ki-67 asONs for inhibiting renal tumor growth.
- Provides evidence for Ki-67 as a suitable antiproliferative target in oncology.
- Supports the development of asON-based therapies for renal cell carcinoma.
