nitrophenols and oblimersen

B-cell lymphoma 2 (Bcl-2) is a regulator protein involved in apoptosis. In the past few decades, this protein has been demonstrated to have high efficacy in cancer therapy, and several approaches targeting Bcl-2 have been tested clinically (e.g., oblimersen, ABT-737, ABT-263, obatoclax mesylate, and AT-101). This review reports potential Bcl-2 inhibitors according to current information on their underlying mechanism and the results of clinical trials. In addition, the function and mechanisms of other potentially valuable Bcl-2 inhibitors that did not show efficacy in clinical studies are also discussed. This summary of the development of Bcl-2 inhibitors provides worthwhile viewpoints on the use of biomedical approaches in future cancer therapy.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Gossypol; Humans; Lymphoma, B-Cell; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thionucleotides

Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms.. PubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology.. To date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(-)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors.. Antiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Clinical Trials as Topic; Gossypol; Humans; Molecular Targeted Therapy; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thionucleotides; Urogenital Neoplasms

The B-cell lymphoma/leukemia 2 (BCL-2) family of proteins has attracted the attention of cancer biologists since the cloning of BCL-2 more than 25 years ago. In the intervening decades, the way the BCL-2 family controls commitment to programmed cell death has been greatly elucidated. Several drugs directed at inhibiting BCL-2 and related antiapoptotic proteins have been tested clinically, with some showing considerable promise, particularly in lymphoid malignancies. A better understanding of the BCL-2 family has also provided insight into how conventional chemotherapy selectively kills cancer cells and why some cancers are more chemosensitive than others. Further exploitation of our understanding of the BCL-2 family promises to offer improved predictive biomarkers for oncologists and improved therapies for patients with cancer.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Drug Resistance, Neoplasm; Humans; Indoles; Molecular Targeted Therapy; Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides; Treatment Outcome

Defects in apoptotic pathways can promote cancer cell survival and also confer resistance to antineoplastic drugs. One pathway being targeted for antineoplastic therapy is the anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that bind to and inactivate BH3-domain pro-apoptotic proteins. Signals transmitted by cellular damage (including antineoplastic drugs) or cytokine deprivation can initiate apoptosis via the intrinsic apoptotic pathway. It is controversial whether some BH3-domain proteins (Bim or tBid) directly activate multidomain pro-apoptotic proteins (e.g., Bax and Bak) or act via inhibition of those anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B) that stabilize pro-apoptotic proteins. Overexpression of anti-apoptotic Bcl-2 family members has been associated with chemotherapy resistance in various human cancers, and preclinical studies have shown that agents targeting anti-apoptotic Bcl-2 family members have preclinical activity as single agents and in combination with other antineoplastic agents. Clinical trials of several investigational drugs targeting the Bcl-2 family (oblimersen sodium, AT-101, ABT-263, GX15-070) are ongoing. Here, we review the role of the Bcl-2 family in apoptotic pathways and those agents that are known and/or designed to inhibit the anti-apoptotic Bcl-2 family of proteins.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Gossypol; Humans; Indoles; Mitochondria; Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides

Cancer cells show deviant behavior that induces apoptotic signaling. To survive, cancer cells typically acquire changes enabling evasion of death signals. One way they do this is by increasing the expression of anti-apoptotic BCL-2 proteins. Anti-apoptotic BCL-2 family proteins antagonize death signaling by forming heterodimers with pro-death proteins. Heterodimer formation occurs through binding of the pro-apoptotic protein's BH3 domain into the hydrophobic cleft of anti-apoptotic proteins. The BH3 mimetics are small molecule antagonists of the anti-apoptotic BCL-2 members that function as competitive inhibitors by binding to the hydrophobic cleft. Under certain conditions, antagonism of anti-apoptotic BCL-2 family proteins can unleash pro-death molecules in cancer cells. Thus, the BH3 mimetics are a new class of cancer drugs that specifically target a mechanism of cancer cell survival to selectively kill cancer cells.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Binding, Competitive; Biphenyl Compounds; Clinical Trials as Topic; Dimerization; Drug Delivery Systems; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Indoles; Mice; Mitochondria; Multigene Family; Neoplasm Proteins; Neoplasms; Nitrophenols; Piperazines; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Structure-Activity Relationship; Sulfonamides; Sulfones; Thionucleotides

Although the philosophy of management of patients with chronic lymphocytic leukaemia (CLL) has been altered with the advent of fludarabine-based therapies, impact on long-term survival is unclear and a significant proportion of patients will develop resistance to fludarabine. Similar to other haematological malignancies, a potential for 'cure' is likely to be achieved only if 'high-quality' complete remissions (CRs) are achieved. Treatment options for patients who develop resistance to fludarabine continue to be limited, with only a proportion obtaining a response (usually not CRs) with salvage therapies. This review summarises novel therapies that are being evaluated in patients with CLL, specifically those targeting the antiapoptotic Bcl-2 family of proteins and receptors (e.g., CD40, CD80, HLA-DR) involved in mediating survival signals from the microenvironment.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; B7-1 Antigen; Biphenyl Compounds; Clinical Trials as Topic; Drug Evaluation, Preclinical; HLA-DR Antigens; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Nitrophenols; Oligonucleotides, Antisense; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sialic Acid Binding Ig-like Lectin 2; Signal Transduction; Sulfonamides; Thionucleotides

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cytochromes c; Drugs, Investigational; Glycolysis; Hexanones; Humans; Mitochondria; Mitochondrial Proton-Translocating ATPases; Neoplasms; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thionucleotides