Chemosensitisation of malignant melanoma by BCL2 antisense therapy

Jansen, Burkhard; Wacheck, Volker; Heere-Ress, Elisabeth; Schlagbauer-Wadl, Hermine; Höeller, Christoph; Lucas, Trevor; Hoermann, M.; Hollenstein, Ursula; Wolff, Klaus; Pehamberger, Hubert

doi:10.1016/s0140-6736(00)03207-4

Cited by 459 publications

(223 citation statements)

References 19 publications

Supporting

Mentioning

209

Contrasting

Unclassified

Order By: Relevance

“…For an antisense-based, gene therapeutic approach, however, viral vectors and antisense RNA expression are needed. For melanoma, clinical studies using antisense oligonucleotides against the antiapoptotic Bcl-2 are on the way aiming the sensitisation of tumour cells against chemotherapy (Jansen et al, 2000). Several other genes were targeted in melanoma cells by in vitro studies, as the anti-apoptotic factor survivin (Grossman et al, 1999), the transcription factor c-myc (Citro et al, 1998) and the growth factor pleiotrophin (Satyamoorthy et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1

Eberle

et al. 2002

Br J Cancer

View full text Add to dashboard Cite

Control of translation initiation was recognised as a critical checkpoint for cell proliferation and tumorigenesis. In human melanoma cells, we have previously reported consistent overexpression of translation initiation factor eIF-4A1. Here, we investigated by transfection of antisense constructs its significance for the control of melanoma cell growth. The tetracyclineinducible expression system was established in melanoma cells, and three fragments of the 5'-, central-, and 3'-portion of the eIF-4A1 cDNA were subcloned in antisense and in sense orientation after a tetracycline inducible promoter. Significant proliferation decrease was obtained after transient transfection and induction of antisense RNA directed against the 5'-and the central portion (up to 10%), whereas, no effects were seen after induction of the 3'-fragment and the sense controls. Cell clones stably transfected with the central antisense fragment revealed after doxycycline induction reduced expression of endogeneous eIF-4A1 mRNA correlated with decreased proliferation rates (up to 6%). These data demonstrate the applicability of antisense strategies against translation factors in melanoma cells. Translation initiation factor eIF-4A1 contributes to the control of melanoma cell proliferation and may be taken into consideration when scheduling new therapeutic approaches targeting the translational control.

show abstract

Section: Discussionmentioning

confidence: 99%

Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1

Eberle

et al. 2002

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Previous RNA-based therapeutics demonstrated partial efficacy against metastatic melanoma in clinical trials, such as targeting BCL2 with the antisense oligonucleotide Oblimersen (Jansen et al, 2000). This limited success has been partly attributed to functional redundancy between cellular pathways responsible for proliferative, proinvasive and survival signals.…”

Section: Targeting Liver Metastasis With Anti-mir-182mentioning

confidence: 99%

“…Although novel targeted therapies such as BRAF inhibitors (Yang et al, 2010) and anti-CTLA4 antibodies (Camacho et al, 2009) are showing promising results in melanoma clinical trials, resistance to these compounds and patient relapse are rapidly emerging (Poulikakos et al, 2010). Small interfering RNA-mediated therapies, such as targeting BCL2 with the antisense oligonucleotide Oblimersen (Jansen et al, 2000), also had limited success. Failure was partly attributed to defective delivery, as well as to functional redundancy between cellular pathways responsible for survival.…”

Section: Introductionmentioning

confidence: 99%

Efficient in vivo microRNA targeting of liver metastasis

et al. 2010

View full text Add to dashboard Cite

Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2 0 sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNAcontrolled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

show abstract

“…59 This has been translated into clinical phase I/IIa studies in which 6 of 14 treated patients showed an anti-tumor response associated with low Bcl-2 levels and increased apoptosis in melanoma biopsies. 60 To discover whether these findings might lead to a novel approach to overcoming drug resistance in melanoma by modulation of apoptotic pathways, further detailed in vitro and in vivo as well as clinical controlled studies are required.…”

Section: Drug Resistance Via Modulation Of the Apoptotic Pathwaymentioning

confidence: 99%

Drug-resistance in human melanoma

Helmbach¹,

Rossmann²,

Kern³

et al. 2001

Int. J. Cancer

162

137

View full text Add to dashboard Cite

Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective due in part to the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with anti-neoplastic agents. The reasons for the chemoresistant phenotype are unknown. The relevance of well-analyzed drug-resistance mechanisms, e.g., intracellular/ extracellular transport and induction of certain enzyme systems, is reviewed. Most anti-cancer drugs kill susceptible cells through induction of apoptosis. Therefore, it appears that differences in the apoptotic pathways which lead to apoptotic deficiency may account for the ability of some tumor cells to resist drug therapy. Human melanomas, which are characteristically drug-resistant, are more likely to have altered apoptotic pathways and fewer pro-apoptotic molecules. Tumor cells with these characteristics are seldom sensitive to drugs. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may have a variety of possibilities for regulating apoptosis and generating apoptotic deficiency. Thus, apoptosis and apoptotic deficiency should be analyzed to better clarify the mechanisms of melanoma resistance.

show abstract

Chemosensitisation of malignant melanoma by BCL2 antisense therapy

Cited by 459 publications

References 19 publications

Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1

Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1

Efficient in vivo microRNA targeting of liver metastasis

Drug-resistance in human melanoma

Contact Info

Product

Resources

About