摘要:

Purpose of reviewTo examine the links of nuclear factor-&kgr;B (NF-&kgr;B) to treatment-induced signaling in breast cancer and to propose further studies to elucidate the role of NF-&kgr;B in breast cancer response to chemotherapy and radiation.Recent findingsThe authors' group and others have investigated the clinical relevance of ubiquitously expressed NF-&kgr;B in breast cancer. Possibly through its effects on apoptosis, NF-&kgr;B has been implicated in tumor resistance to chemotherapy and radiation in many types of tumors. Furthermore, bothin vitroandin vivostudies have shown that targeted inhibition of NF-&kgr;B can sensitize tumor cells to chemotherapy and radiation.SummaryThe molecular mechanisms involved in chemotherapy-induced and radiation-induced cell death in breast cancer are not fully known, nor are the mechanisms of treatment resistance. NF-&kgr;B is a transcription factor for a number of genes involved in tumor progression and resistance to systemic therapies and is a major regulator of the apoptotic pathway. Gaining further insights into molecular factors such as NF-&kgr;B as biomarkers for treatment response may help clinicians predict treatment outcome and lead to the development of targeted therapeutics.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe discovery of temozolomide in the 1980s was expected to be an important advance in improving survival for patients with malignant brain tumors. Numerous clinical studies have demonstrated the activity of temozolomide against recurrent or refractory gliomas and noncentral nervous system malignancies. In the last 2 years, studies have focused on exploring strategies to optimize the efficacy of temozolomide, including evaluating different temozolomide dosing schedules and combining temozolomide with other antineoplastic agents, radiation therapy, or drug resistance-modifying agents.Recent findingsA critical review of these studies suggests that temozolomide, as currently used, has limited efficacy in treating refractory malignant infiltrative brain tumors, and survival benefit is, at best, a few weeks longer than that with procarbazine. There is enthusiasm about the activity of temozolomide in the treatment of recurrent low-grade gliomas and advanced malignant melanomas. Temozolomide has activity and a favorable safety profile in all dosing schedules tested. Nevertheless, the trials evaluating the efficacy of temozolomide suffer from being uncontrolled, with short follow-up periods.SummaryDespite the advantages of a favorable safety profile and oral administration, temozolomide has yet to realize its initial promise and full potential. Studies of temozolomide combined with novel drug resistance-modifying agents will likely improve disease control while minimizing toxicities, leading to improved survival benefit. Larger, randomized trials comparing temozolomide with standard therapy are needed to confirm the suggested benefit from temozolomide in malignant brain tumors. Temozolomide will continue to be attractive as an agent in the treatment of brain tumors because of its desirable features and safety.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewHeat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, or overexpressed signaling proteins, which promote cancer cell growth or survival or both. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising antitumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial, and several Phase II trials are in progress. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival.Recent findingsRecently identified clients of Hsp90 participate, frequently in overlapping pathways, in mediating cancer cell survival. These include Akt, Her2, and HIF-1&agr;. Thus, by inhibiting multiple survival pathways used by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase thein vivoefficacy of the standard agent. Furthermore, Hsp90 modulates androgen receptor activity and the activity of several mutated kinases characteristic of several leukemias and lymphomas, making Hsp90 inhibition an attractive modality in these cases.SummaryHsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should augment the treatment of multiple forms of cancer.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of review2-Methoxyestradiol (2ME2) is a natural metabolite of estradiol with antiangiogenic and antitumor activities. The ability of 2ME2 to target both tumor cells and neovasculature in preclinical models led to ongoing evaluations of 2ME2 in clinical trials. This brief review focuses on recent progress with 2ME2, specifically the effectiveness of 2ME2 in diverse tumor types, new mechanistic information that clarifies the multiple cellular effects of 2ME2, and the identification of promising 2ME2 analogues.Recent findingsNew preclinical data show that 2ME2 has a broader spectrum of antitumor activities than first anticipated and suggest that 2ME2 may have utility in treating multiple myeloma, sarcoma, and other solid tumors. The mechanisms of action of 2ME2 are complex and still unclear. Recent mechanistic studies indicate that the pleiotropic activities of 2ME2 are not mediated through &agr; and &bgr; estrogen receptors. 2ME2's actions are mediated through inhibition of the proangiogenic transcription factor hypoxia-inducible factor 1&agr;, c-Jun NH2-terminal kinase signaling, and the generation of reactive oxygen species. Both the intrinsic and extrinsic apoptotic pathways are initiated by 2ME2. Although the relative roles of each pathway vary with specific cell types, this may help explain 2ME2's wide spectrum of activity.SummaryIn summary, preclinical studies continue to provide enthusiasm for 2ME2 as a broad-spectrum agent. New data help resolve the roles of the diverse cellular effects of 2ME2 including microtubule disruption, initiation of signal transduction pathways, and generation of reactive oxygen species, which culminate in induction of apoptosis. 2ME2 analogues with superior properties have been identified and may provide opportunities for second-generation drugs.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewInterferons are pleiotropic cytokines that exhibit important biologic activities, including antiviral, antitumor, and immunomodulatory effects. These cytokines have found important applications in clinical medicine, including the treatment of certain malignancies. The purpose of this review is to provide an update on basic and clinical research in the interferon field.Recent findingsSignificant advances have recently occurred in the field of type I interferon signal transduction. It is well known that the interferons transduce signals via activation of multiple signaling cascades, involving Jak kinases, signal transducer and activator of transcription proteins, Map kinases, and IRS and Crk proteins. Recent evidence indicates that the p38 Map kinase pathway plays an important role in type I interferon signaling in malignant cells and that its function is required for type I interferon-dependent gene transcription and generation of the antiproliferative of type I interferons. In clinical oncology, interferon-&agr; remains an active and useful agent in the treatment of several malignant disorders, and efforts are underway to improve its efficacy by using different schedules and combinations with other agents.SummaryThis review summarizes the mechanisms of signal transduction of interferons and the emerging new concepts in this area. An update on the clinical applications of interferons in oncology is also provided, and potential translational applications, reflecting recent advances in the field, are discussed.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewCancer treatment is entering an era of targeted approaches. One such approach is use of the immune system to recognize and eliminate malignant cells. Synthetic CpG oligonucleotides (CpG DNA) are a relatively new class of agents that have the ability to stimulate a potent, orchestrated tumor-specific immune response. This review provides an overview of the immunologic effects of CpG DNA and summarizes the results of preclinical investigations that have led to ongoing development of CpG DNA as a component of clinical cancer immunotherapy.Recent findingsNew studies demonstrate that at least three classes of CpG DNA sequences exist, each with different physical characteristics and biologic effects. Preliminary studies in several animal models of cancer suggest that CpG DNA have the ability to induce tumor regression by activating innate immunity, enhancing antibody dependent cellular cytotoxicity, and serving as potent vaccine adjuvants that elicit a specific, protective immune response.SummaryAnimal models suggest that CpG DNA may have many uses in cancer immunotherapy. Early clinical trials suggest that CpG DNA can be administered safely to humans, and studies are ongoing to understand how these agents may play a role in cancer immunotherapy.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewDecitabine is a cytosine analogue synthesized in the 1960s that is currently enjoying a revival of interest prompted by the elucidation of DNA methylation inhibition as its major mechanism of action, along with increased understanding of the role of DNA methylation in epigenetic dysregulation in cancer. These advances have turned this agent from just another cytosine analogue into a targeted drug aimed at reversing epigenetic silencing in cancer cells. Here, recent clinical and translational studies with decitabine are reviewed.Recent findingsScientists are now taking a closer look at this drug as a targeted agent, with particular attention to schedules of administration and mechanisms ofin vivoefficacy. Two phase II trials have reported substantial clinical activity of decitabine in the myelodysplastic syndrome and in chronic myelogenous leukemia. There is considerable interest in combining decitabine with histone deacetylase inhibitors and in using it to sensitize cells to chemotherapy or to biologic therapy. Finally, ongoing efforts are deciphering thein vivomechanisms of responses seen after decitabine administration.SummaryDecitabine, an old drug, has now made a comeback as a targeted agent and a prototype for epigenetic therapy in cancer. Doses, schedules of administration, and the development of rational combinations including this agent must all take this critical mechanism of action into account.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewDuring 2003, the first randomized trials were published comparing adjuvant platin-based chemotherapy versus no treatment in early epithelial ovarian cancer.Recent findingsRecent findings of the European Organisation for Research and Treatment of Cancer Adjuvant ChemoTherapy In Ovarian Neoplasm and International Collaborative Ovarian Neoplasm-1 trials showed an improvement of overall survival of 8% in patients treated with adjuvant platin-based chemotherapy compared with observation. In a subgroup analysis, in 150 optimally surgically staged patients of the European Organisation for Research and Treatment of Cancer Adjuvant ChemoTherapy In Ovarian Neoplasm trial, there appears to be no benefit of adjuvant chemotherapy. In past years, it has been shown that degree of differentiation is a much stronger predictor of recurrence in early ovarian cancer than International Federation of Gynaecology and Obstetrics subclassification (Ia, Ib, Ic). It has also been shown that patients with bilateral tumors (Ib) have the same prognosis as International Federation of Gynaecology and Obstetrics stage Ic patients.SummaryDuring the past year, it has been shown that platin-based adjuvant chemotherapy improves recurrence-free and overall survival in early epithelial ovarian cancer. It should be emphasized, however, that this was demonstrated in patients in whom the true nature of early stage disease was doubtful in many patients due to incomplete surgical staging. In a subgroup of patients who are optimally surgically staged, adjuvant chemotherapy may be less effective. Theoretically, only a future trial randomizing optimal surgical staging versus adjuvant chemotherapy may be able to provide definitive conclusions, but such a trial would be almost impossible to conduct. In the meantime, optimal staging is advocated in all patients who are fit enough to undergo this procedure. Degree of differentiation should be incorporated in a new International Federation of Gynaecology and Obstetrics classification for stage I disease and in clinical decision making.

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:1040-8746    

出版商:OVID    

年代:2003

数据来源: OVID