Phase I Clinical and Pharmacokinetic Study of Bcl-2 Antisense Oligonucleotide Therapy in Patients With Non-Hodgkin’s Lymphoma

Waters, Justin S.; Webb, Andrew R.; Cunningham, David; Clarke, Paul A.; Raynaud, Florence I.; Stefano, Francesca Di; Cotter, Finbarr E.

doi:10.1200/jco.2000.18.9.1812

Cited by 406 publications

(200 citation statements)

References 23 publications

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“…Antisense oligonucleotides targeting bcl-2 have been used to reduce the expression of bcl-2 in phase 1 clinical trials with lymphomas (Waters et al, 2000). This strategy could be used to reduce the expression of bcl-2 or bcl-X L in cancers that are predicted to be radioresistant.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 expression predicts radiotherapy failure in laryngeal cancer

et al. 2005

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Early stage laryngeal cancer can be effectively cured by radiotherapy or conservative laryngeal surgery. In the UK, radiotherapy is the preferred first line treatment. However, up to 25% of patients with T2 tumours will demonstrate locally persistent or recurrent disease at the original site, requiring salvage surgery to achieve a definitive cure. Patients experiencing treatment failure have a relatively poor prognosis. A retrospective analysis was conducted consisting of 124 patients with early stage (T1 -T2, N0) laryngeal squamous cell carcinoma. In total, 62 patients who failed radiotherapy were matched for T stage, laryngeal subsite and smoking history to a group of 62 patients successfully cured by radiotherapy. Using immunohistochemistry the groups were compared for expression of apoptotic proteins: bcl-2, bcl-X L , bax, bak and survivin. Radioresistant laryngeal cancer was associated with bcl-2 (Po0.001) and bcl-X L (P ¼ 0.005) expression and loss of bax expression (P ¼ 0.012) in pretreatment biopsies. Bcl-2 has an accuracy of 71% in predicting radiotherapy outcome. The association between expression of bcl-2, bcl-X L and bax with radioresistant cancer suggests a potential mechanism by which cancer cells avoid the destructive effects of radiotherapy. Predicting radioresistance, using bcl-2, would allow the clinician to recommend conservative laryngeal surgery as an alternative first line treatment to radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Bcl-2 expression predicts radiotherapy failure in laryngeal cancer

et al. 2005

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“…The first and most developed strategy involves antisense oligonucleotides which are chemically modified stretches of single-strand DNA forming specific RNA-DNA duplex with the targeted messenger RNA, thus leading to its RNase H-mediated cleavage and inhibition of the gene expression. An 18-mer phorphorothioate antisense oligonucleotide complementary of the first six codons of the initiating sequence of the human bcl-2 mRNA demonstrated encouraging preclinical results (Jansen et al, 1998) and was initially tested in patients with lymphoma, which identified some dose-limiting toxicities such as thrombocytopenia (likely due to the phosphorothioate backbone of the antisense molecule) and hypotension (Waters et al, 2000). Phase I/II trials of Genasense in combination with classical cytotoxic drugs provided encouraging results (Rudin et al, 2004) but phase III trials in diseases such as chronic lymphocytic leukemias, multiple myelomas and melanomas did not demonstrate sufficient benefits to offset the toxicity and so far, the Federal Drug Administration in US did not approve Oblimersen as an anticancer drug (Letai, 2005).…”

Section: Molecules Developed To Target the Mitochondriamentioning

confidence: 99%

Mitochondria in hematopoiesis and hematological diseases

et al. 2006

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“…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). More recently, small molecules that target the BH3-domain-binding site of Bcl-2 have been developed as Bcl-2 inhibitors (Wang et al, 2000;Oltersdorf et al, 2005).…”

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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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Phase I Clinical and Pharmacokinetic Study of Bcl-2 Antisense Oligonucleotide Therapy in Patients With Non-Hodgkin’s Lymphoma

Abstract: Bcl-2 antisense therapy is feasible and shows potential for antitumor activity in NHL. Downregulation of Bcl-2 protein suggests a specific antisense mechanism.

Cited by 406 publications

References 23 publications

Bcl-2 expression predicts radiotherapy failure in laryngeal cancer

Bcl-2 expression predicts radiotherapy failure in laryngeal cancer

Mitochondria in hematopoiesis and hematological diseases

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

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