Unraveling biologic therapy for Bcl-2-expressing malignancies

doi:10.1053/j.seminoncol.2004.10.014

Seminars in Oncology

Volume 31, Supplement 16, December 2004, Pages 18-21

https://doi.org/10.1053/j.seminoncol.2004.10.014 Get rights and content

Cancer cells that express excessive levels of Bcl-2 pose a major problem in the delivery of curative therapy. Most treatments for such cancer involve chemotherapy to induce the apoptotic process. While these therapies often result in disease control for periods of time, failure to initiate apoptosis as a result of acquired resistance limits the effectiveness of treatment for many common hematopoietic and solid malignancies, and ultimately death from the malignancy still occurs. Various anti-apoptotic proteins of the Bcl-2 family that localize to the mitochondria appear to be involved in this resistance mechanism. However, recent advances in the understanding of malignant cell biology, achieved through both genomics and proteomics, have made it possible to explore novel approaches directed at re-establishing sensitivity to chemotherapy, presenting an attractive strategy for cancer treatment. In this article we discuss how this may be achieved by lowering Bcl-2 anti-apoptotic protein expression using antisense oligonucleotides or, alternatively, by functionally antagonizing Bcl-2 using ligands of the mitochondrial benzodiazepine receptor.

Section snippets

Bcl-2

The bcl-2 (B-cell lymphoma/leukemia-2) oncogene was initially recognized for its role in blocking apoptosis in certain B-cell lymphomas. More recently, Bcl-2 has been shown to also be overexpressed in most types of cancer, including breast, colorectal, lung, and prostate cancers, as well as melanoma. Bcl-2 belongs to a family of evolutionarily conserved proteins that is functionally subdivided into proapoptotic (eg, Bax, Bak) and anti-apoptotic members (eg, Bcl-2, Bcl-X_L). Bcl-2 family members

Oblimersen: Bcl-2 antisense

Bcl-2 antisense oligonucleotides have been successfully used to block expression of Bcl-2 both in vitro and in vivo and to lift the blockage of apoptosis in cancer cells.1 Antisense oligonucleotides are short, synthetic, single-stranded DNA sequences that bind to mRNA; this binding accelerates mRNA decay and thus effectively blocks protein synthesis.1 A range of antisense oligonucleotides for Bcl-2 inhibition have been studied, and oblimersen (Genasense, formerly G3139; Genta, Inc, Berkeley

Other therapeutics that downregulate Bcl-2

Another approach for downregulating Bcl-2 activity in cancer cells is to target the mBzR (also called the peripheral benzodiazepine receptor). This 18-kd transmembrane-spanning protein localized to the outer mitochondrial membrane shares a close physical association with constituents of the MPTP. Two small molecules that block the activity of the mBzR are currently being investigated. PK11195, an isoquinoline carboxamide, specifically binds the mBzR with nanomolar affinity. This binding affects

Other antiapoptotic targets

In addition to Bcl-2, it may be necessary to target other anti-apoptotic molecules that inhibit apoptosis in the treatment of certain cancers. For example, NF-κB, which is part of the ubiquitin-proteasome pathway, is overexpressed in many types of malignancies, leading to chemoresistance via the MPTP and the caspase-9 pathway. Even in the presence of Bcl-2 inhibition, NF-κB can potentially block the caspase cascade. Therefore, in cancer cells overexpressing Bcl-2 and demonstrating NF-κB

Conclusion

A critical factor for treating chemotherapy-resistant malignancies is controlling mitochondrial permeability, which is essentially a gatekeeper of apoptosis. In the future, it is expected that biologic therapies that target the apoptotic machinery and the MPTP will be based on those currently investigated in or considered for clinical trials. An improved understanding of malignant cell biology will provide further opportunities to progress from chemotherapy-based treatments to biologic

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¹: Dr Cotter has received honoraria from Aventis, Genta, and Genentech BioOncology.

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Unraveling biologic therapy for Bcl-2-expressing malignancies

Section snippets

Bcl-2

Oblimersen: Bcl-2 antisense

Other therapeutics that downregulate Bcl-2

Other antiapoptotic targets

Conclusion

J Biol Chem

Lancet

Exp Cell Res

Leuk Res

Mod Pathol

Controlling the mitochondrial gatekeeper for effective chemotherapy

Br J Haematol

Biochemical and cellular mechanisms of toxic liver injury

Semin Liver Dis

Bcl-2 antisense oligodeoxynucleotide therapy of Epstein-Barr virus-associated lymphoproliferative disease in severe combined immunodeficient mice

Cancer Res

Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma

J Clin Oncol

A phase I-II study with dacarbazine and BCL-2 antisense oligonucleotide G3139 (GENTA) as a chemosensitizer in patients with advanced malignant melanoma

Proc Am Soc Clin Oncol

A phase I/IIA dose-escalating trial of bcl-2 antisense (G3139) treatment by 14-day continuous intravenous infusion (CI) for patients with androgen-independent prostate cancer or other advanced solid tumor malignancies

Proc Am Soc Clin Oncol

Tumor regression of human breast carcinomas by combination therapy of anti-bcl-2 antisense oligonucleotide and chemotherapeutic drugs

Proc Am Assoc Cancer Res

A phase I study of BCL-2 antisense G3139 (GENTA) and weekly docetaxel in patients with advanced breast cancer and other solid tumors

Proc Am Soc Clin Oncol

Bcl-2 antisense (Genasense) induces apoptosis and potentiates activity of both cytotoxic chemotherapy and rituximab in primary CLL cells

Blood

Genasense targeting Bcl-2 protein expression enhances the biological anti-tumor activity of rituximab against non-Hodgkins (NHL) cell lines and lymphoma xenografts

Blood