Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides

Dias, Nathalie; Stein, C. A.

doi:10.1016/s0939-6411(02)00060-7

Cited by 86 publications

(56 citation statements)

References 56 publications

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“…10). G3139-induced tumor regression without dose-limiting toxicity was also observed in other tumors, e.g., melanoma, lymphoma, or gastric cancers (11). Synergism of the G3139 and anticancer drugs was also shown in different tumors, including human melanoma (7,12,13).…”

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confidence: 86%

Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease

Mena

Benlloch

Ortega

et al. 2007

Clinical Cancer Research

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Purpose: Advanced melanoma resists all current therapies, and metastases in the liver are particularly problematic. Prevalent resistance factors include elevated glutathione (GSH) and increased expression of bcl-2 in melanoma cells. GSH has pleiotropic effects promoting cell growth and broad resistance to therapy, whereas Bcl-2 inhibits the activation of apoptosis and contributes to elevation of GSH. This study determined the in vivo efficacy of combination therapies administered while GSH and Bcl-2 were individually and simultaneously decreased in metastatic melanoma lesions. Experimental Design: Highly metastatic murine B16 melanoma (B16M-F10) cells have elevated levels of both GSH and Bcl-2. B16M-F10 cells were injected i.v. to establish metastatic lesions in vivo. GSH was decreased using an L-glutamine^enriched diet and administration of verapamil and acivicin, whereas Bcl-2 was reduced using oligodeoxynucleotide G3139. Paclitaxel, X-rays, tumor necrosis factor-a, and IFN-g were administered as a combination therapy. Results: Metastatic cells were isolated from liver to confirm the depletion of GSH and Bcl-2 in vivo. Reduction of Bcl-2 and GSH, combined with partial therapies, decreased the number and volume of invasive B16M-F10 foci in liver by up to 99% (P < 0.01). The full combination of paclitaxel, X-rays, and cytokines eliminated B16M-F10 cells from liver and all other systemic disease, leading to long-term survival (>120 days) without recurrence in 90% of mice receiving the full therapy.Toxicity was manageable; the mice recovered quickly, and hematology and clinical chemistry data were representative of accepted clinical toxicities. Conclusions: Our results suggest a new strategy to induce regression of late-stage metastatic melanoma.

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confidence: 86%

Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease

Mena

Benlloch

Ortega

et al. 2007

Clinical Cancer Research

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“…These agents are discussed below as well as others designed to target molecules that can lead not only to apoptosis, but also to alternative cell death pathways (Table 2). [90]. Oblimersen was not approved for treatment of melanoma because results from phase III trials showed it did not extend survival [89].…”

Section: Targeted Approaches To Activating Cell Deathmentioning

confidence: 99%

Chemotherapeutic Approaches for Targeting Cell Death Pathways

2006

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Learning Objectives After completing this course, the reader will be able to: List the multiple cell death pathways that are activated in response to chemotherapeutic agents. Identify signaling molecules involved and morphological changes that occur in the different types of cell death pathways. Describe mechanisms targeted by novel chemotherapeutic agents. Access and take the CME test online and receive 1 AMA PRA category 1 credit at http://CME.TheOncologist.com For several decades, apoptosis has taken center stage as the principal mechanism of programmed cell death in mammalian tissues. It also has been increasingly noted that conventional chemotherapeutic agents not only elicit apoptosis but other forms of nonapoptotic death such as necrosis, autophagy, mitotic catastrophe, and senescence. This review presents background on the signaling pathways involved in the different cell death outcomes. A re‐examination of what we know about chemotherapy‐induced death is vitally important in light of new understanding of nonapoptotic cell death signaling pathways. If we can precisely activate or inhibit molecules that mediate the diversity of cell death outcomes, perhaps we can succeed in more effective and less toxic chemotherapeutic regimens.

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“…Antisense oligonucleotides are a targeted therapeutic approach to suppress translation of complementary gene transcripts (12,13). Cenersen, a 20-mer antisense phosphorothioate oligonucleotide,…”

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confidence: 99%

TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

Cáceres

McGraw

Yip

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore erythropoiesis in del(5q) MDS. Cenersen treatment of ribosomal protein S-14-deficient erythroblasts significantly reduced cellular p53 and p53-up-regulated modulator of apoptosis expression compared with controls, accompanied by a significant reduction in apoptosis and increased cell proliferation. In a two-stage erythroid differentiation assay, cenersen significantly suppressed nuclear p53 in bone marrow CD34+ cells isolated from patients with del(5q) MDS, whereas erythroid burst recovery increased proportionally to the magnitude of p53 suppression without evidence of del(5q) clonal suppression (r = −0.6; P = 0.005). To explore the effect of p53 suppression on erythropoiesis in vivo, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, was added to lenalidomide treatment in eight lower-risk, transfusion-dependent, del(5q) MDS patients with acquired drug resistance. Transfusion independence was restored in five patients accompanied by expansion of erythroid precursors and decreased cellular p53 expression. We conclude that targeted suppression of p53 could support effective erythropoiesis in lenalidomide-resistant del(5q) MDS.

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Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides

Cited by 86 publications

References 56 publications

Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease

Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease

Chemotherapeutic Approaches for Targeting Cell Death Pathways

TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

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