Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines

Selzer, Edgar; Schlagbauer-Wadl, Hermine; Okamoto, Ichiro; Pehamberger, Hubert; Pötter, Richard; Jansen, Burkhard

doi:10.1097/00008390-199806000-00001

Cited by 124 publications

(92 citation statements)

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“…38 Several authors have reported expression of the apoptosissuppressing gene product Bcl-x L in human malignant melanoma. 15,39 Leiter et al 13 demonstrated that Bcl-x L is universally expressed in metastatic melanoma. However, the role of Bcl-x L in the chemoresistance of human melanoma has not been reported despite the clear expression of this protein in melanoma and its link to melanoma progression.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14] Bcl-x L is ubiquitously expressed in melanoma metastases and in Ͼ90% of primary melanomas. 13,15 Since the balance between cell survival and death is determined by the competitive action of death agonists like Bax and antagonists such as Bcl-x L and Bcl-2, any approach to alter this balance in favor of cell death during chemotherapy could have therapeutic benefit. AS oligonucleotides are chemically modified stretches of single-stranded DNA complementary to mRNA regions of target genes that specially inhibit gene expression by the formation of DNA/RNA hybrids.…”

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confidence: 99%

“…The chemosensitivity of human hepatoblastoma cells to paclitaxel (Taxol) and doxorubicin was not affected by Bcl-2 levels, while reduction of Bcl-x L levels rendered the cells more sensitive to these drugs. 29 The findings outlined above and the ubiquitous expression of Bcl-x L in melanoma metastases 13,15 suggest that Bcl-x L represents a suitable molecular target for AS oligonucleotide treatment in human melanoma. Our preclinical study builds on this notion and investigates whether Bcl-x L expression confers additional chemoresistance in an experimental melanoma system and whether Bcl-x L AS treatment increases chemosensitivity in this setting.…”

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confidence: 99%

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Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Heere-Ress

Thallinger

Lucas

et al. 2002

Intl Journal of Cancer

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Malignant melanoma is a tumor that responds poorly to a variety of apoptosis-inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl-x L is an antiapoptotic member of the Bcl-2 family and is universally expressed in human melanoma. To evaluate the Bcl-x L protein as a potential therapeutic target in melanoma, the influence of Bcl-x L expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl-x L in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin-induced apoptosis (p < 0.05). In a parallel approach, reduction of Bcl-x L protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy-induced apoptosis. These data suggest that Bcl-x L is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl-x L expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Heere-Ress

Thallinger

Lucas

et al. 2002

Intl Journal of Cancer

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“…Human melanoma primary tumors express Bcl-2 in up to 90% of all cases. 56 High expression of Bcl-2 has been correlated with decreased survival and resistance to chemotherapy in human melanomas and other tumors. 57,58 A decrease in Bcl-2 levels or inhibition of Bcl-2 activity leads to an increase in apoptosis or at least in the responsiveness of cells to apoptotic stimuli.…”

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

165

137

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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.

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“…Cancer cells may acquire resistance to temozolomide by a number of mechanisms, including overexpression of O 6 -alkylguanine-DNA alkyltransferase (Lee et al, 1994;Middleton et al, 1998), deficiency or mutation in the mismatch repair (MMR) pathway (D'Atri et al, 1998) and increased expression of proteins that inhibit apoptosis, such as Bcl-2 (Selzer et al, 1998). Temozolomide is well tolerated (Newlands et al, 1992;O'Reilly et al, 1993;Bleehen et al, 1995;Dhodapkar et al, 1997), with thrombocytopaenia as the main toxicity.…”

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Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

et al. 2005

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The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1 -5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m À2 day À1 temozolomide and 225 mg m À2 day À1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

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Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines

Cited by 124 publications

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Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Drug-resistance in human melanoma

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

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Expression of Bcl-2 family members in human melanocytes, in melanoma metastases and in melanoma cell lines

Cited by 124 publications

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Bcl‐XL is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Bcl‐XL is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Drug-resistance in human melanoma

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

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Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy

Bcl‐X_L is a chemoresistance factor in human melanoma cells that can be inhibited by antisense therapy