bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice

Jansen, Burkhard; Schlagbauer-Wadl, Hermine; Brown, Bob D.; Bryan, R. Nick; Elsas, Andrea van; Müller, Markus; Wolff, Klaus; Eichler, Hans‐Georg; Pehamberger, Hubert

doi:10.1038/nm0298-232

Cited by 437 publications

(247 citation statements)

References 11 publications

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“…For example, survivin, a member of the inhibitor of apoptosis protein (IAP) family, was strongly expressed in human melanomas but not in normal melanocytes, and overexpression of survivin in the sentinel lymph nodes from melanoma patients was inversely correlated with patient survival (Grossman et al, 1999;Gradilone et al, 2003). X L , and Mcl-1, may also contribute to melanoma progression and chemoresistance as antisense oligos against these genes can induce death of melanoma cells (Jansen et al, 1998;Heere-Ress et al, 2002;Thallinger et al, 2003). However, the implication of Bcl-2 antiapoptotic proteins as melanoma progression factors is controversial.…”

Section: Discussionmentioning

confidence: 99%

Reduced Apaf-1 expression in human cutaneous melanomas

et al. 2004

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Malignant melanoma is a life-threatening skin cancer due to its highly metastatic character and resistance to radio-and chemotherapy. It is believed that the ability to evade apoptosis is the key mechanism for the rapid growth of cancer cells. However, the exact mechanism for failure in the apoptotic pathway in melanoma cells is unclear. p53, the most frequently mutated tumour suppressor gene in human cancers, is a key apoptosis inducer. However, p53 mutation is only found in 15 -20% of melanoma biopsies. Recently, it was found that Apaf-1, a downstream target of p53, is inactivated in metastatic melanoma. Specifically, loss of heterozygosity (LOH) of the Apaf-1 gene was found in 40% of metastatic melanoma. To determine if loss of Apaf-1 expression is indeed involved in melanoma progression, we employed the tissue microarray technology and examined Apaf-1 expression in 70 human primary malignant melanoma biopsies by immunohistochemistry. Our data showed that Apaf-1 expression is significantly reduced in melanoma cells compared with normal nevi (w 2 ¼ 6.02, P ¼ 0.014). Our results also revealed that loss of Apaf-1 was not associated with the tumour thickness, ulceration or subtype, patient's gender, age and 5-year survival. In addition, our in vitro apoptosis assay revealed that overexpression of Apaf-1 can sensitise melanoma cells to anticancer drug treatment. Taken together, our data indicate that Apaf-1 expression is significantly reduced in human melanoma and that Apaf-1 may serve as a therapeutic target in melanoma.

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Section: Discussionmentioning

confidence: 99%

Reduced Apaf-1 expression in human cutaneous melanomas

et al. 2004

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“…The combination of Bcl-2 oligo-anti-sense (augmerosen, Gentasense, G-3139; Sims Deltec, St. Paul, MN) and dacarbazine improved chemosensitivity of human melanoma xenografts grown in (SCID) mice. 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

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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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“…These proteins are potent inhibitors of cell death, and high expression levels are observed in many cancers (Adams and Cory, 1998;Reed, 1999). Bcl-2 itself is highly expressed in the majority of cases of acute leukaemia, approximately 50% of diffuse large B-cell lymphomas and up to 90% of malignant melanomas (Banker et al, 1997;Jansen et al, 1998;Campos et al, 1999;Skinnider et al, 1999). Forced expression of Bcl-2 results in resistance to a variety of proapoptotic stimuli, including growth factor withdrawal, cytotoxic chemotherapy and radiation, and there is some evidence that Bcl-2 also promotes resistance to anticancer immune responses.…”

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confidence: 99%

“…Antisense oligonucleotides that decrease Bcl-2 expression caused direct tumour suppression and increased sensitivity to cytotoxic chemotherapy in preclinical models (Cotter et al, 1994;Jansen et al, 1998). However, Bcl-2 antisense therapy had limited activity when tested in clinical trials, potentially owing to poor access to the intracellular compartment and inadequate reduction in Bcl-2 expression levels (Waters et al, 2000;Yuen and Sikic, 2000;Morris et al, 2002).…”

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confidence: 99%

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

et al. 2007

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The cytotoxic effects of anticancer immune cells are mediated by perforin/granzyme-B, Fas ligand and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and therefore depend on intact apoptotic responses in target tumour cells. As killing by all three of these mechanisms is blocked by the frequently overexpressed antiapoptotic oncoprotein Bcl-2, we hypothesised that coexposure to a Bcl-2 inhibitor might enhance anticancer immune responses. We evaluated this in U937 lymphoma cells, and A02 melanoma cells, which both show strong Bcl-2 expression. Va24 þ Vb11 þ natural killer T (NKT) cells expanded from peripheral blood of normal donors (n ¼ 3) were coincubated with PKH26-labelled U937 cells, and cytotoxicity was determined by flow cytometry after annexin-V-FITC and 7-AAD staining. In all cases, addition of the HA14-1 small-molecule Bcl-2 inhibitor to the cocultures significantly increased apoptosis in the target U937 cells. Using a similar assay, killing of A02 cells by the cytotoxic T-lymphocyte clone 1H3 was shown to be amplified by coexposure to the potent small-molecule Bcl-2 inhibitor ABT-737. Experiments with immune effectors preincubated with concanamycin-A suggested that sensitisation to perforin/granzyme-B may underlie enhanced target-cell killing observed in the presence of Bcl-2 inhibitors. We conclude that immune destruction of malignant cells can be amplified by molecular interventions that overcome Bcl-2-mediated resistance to apoptosis.

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bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice

Cited by 437 publications

References 11 publications

Reduced Apaf-1 expression in human cutaneous melanomas

Reduced Apaf-1 expression in human cutaneous melanomas

Drug-resistance in human melanoma

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

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