Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) (v.11, #8)
Editorial [Hot Topic: Targeted Therapy for Glioblastoma Multiforme (Guest Editor: Marc-Eric Halatsch)] by Marc-Eric Halatsch (pp. 692-692).
Despite advances in neurosurgical techniques, radio- and chemotherapy, the prognosis of patients with glioblastoma multiforme remainspoor. Against this background, more efficacious adjuvant therapies with less toxicity are urgently needed.While molecularly targeted therapy has evolved as a highly rational and specific approach to meet this requirement, preliminary clinicalresults have fallen short of expectations. Among the reasons for this disappointment is the fact that glioblastoma multiforme is driven by amultitude of differentially activated or silenced signaling pathways with both parallel and converging complex interactions. As a result, theexistence of a single molecular key target conferring unconditional and irreplaceable cellular “oncogene addiction” not only for the majorityof tumor cells, but also in the majority of glioblastoma patients has not been confirmed in clinical settings and must be considered unlikely.To add to this complexity, lack of sometimes even moderate efficacy of targeted therapy strategies in clinical trials may not necessarilyreflect an inappropriate choice of the molecular target itself, but may simply be a consequence of incomplete target inhibition. Therefore,clinical trial designs incorporating molecular in addition to “classical” endpoints will become increasingly important. At the same time,advancement of our currently deficient understanding of what “intrinsic resistance” to targeted therapy really means critically depends onexactly this type of information.It may be expected that bioinformatics research network initiatives will continue to rapidly expand our knowledge of the molecular basisof cancer by defining mutational landscapes and mapping dynamic cross-interactions of multiple signaling pathways. While this undoubtedlyrepresents unprecedented opportunity and challenge in glioblastoma research, the cellular and molecular heterogeneity of glioblastoma islikely to remain a major obstacle to successful implementation of a truly “personalized” therapeutic approach for years and decades ahead.Engaging in this demanding subfield of glioblastoma research may be especially rewarding as some of the future lessons on the basis of“acquired resistance” to targeted therapy will have to be learned by better understanding “heterogeneity”.By merging outstanding contributions of well-recognized experts in their fields, this Special Issue aims at highlighting hopes anddisappointments, changes in paradigms and future perspectives of targeted therapy for glioblastoma multiforme.While the dilemma and limitations of monotargeting are comprehensively analyzed by Karpel et al., Sathornsumetee provides valuableinsights into the potential of multitargeting. These intracellular approaches are thematically complemented by extracellular strategiesinvolving targeted toxins as described in a state-of-the-art review by Candolfi et al. An impressively broad overview regarding nucleic acidbasedtherapeutics afforded by Shir and coauthors is extended and specifically elaborated by Rainov and Heidecke in their insightful work onthe clinical development of experimental virus-mediated gene therapy.Angiogenesis is of eminent importance to the development, maintenance and progression of glioblastoma, and targeted interference withthis complex process has produced sometimes puzzling results. In the maze of targeting angiogenesis, indispensable navigation and guidanceis provided by Linkous and Yazlovitskaya.Seemingly remote from angiogenesis, critical appraisal of the potential of ..III-tubulin as a therapeutic target to prevent or curtailmitogenic division is offered by Katsetos et al. in their thoughtful and timely review.Last not least, Kast and coauthors outline a novel hypotheses-based approach to the treatment of glioblastoma by using a drug already inclinical use for a non-oncological indication. The underlying idea that substances capable of enhancing current standard therapies areavailable and only have to be rededicated is certainly thought-provoking.The contributors have gone to great lengths to reach the ambitious goal of the compilation as a whole, and guest-editing this Issue hastherefore been a tremendous pleasure. This work would not have been possible without the commitment of numerous expert reviewers whomI thank for their thoughtful advice.
Nucleic Acid-Based Therapeutics for Glioblastoma by Alexei Shir, Alexander Levitzki, Ernst Wagner, Shoshana Klein, Manfred Ogris (pp. 693-699).
Nucleic acid based therapeutics offer the possibility of tailor-made treatment of malignant diseases. For recurrent glioblastomamultiforme (GBM), the most aggressive type of brain tumor, no accepted treatment exists, making therapeutically active nucleic acidsa viable option. In this review, current preclinical and clinical studies harnessing the potential of antitumoral nucleic acids for GBMtreatment will be considered. These include gene therapy to over-express antitumoral gene products, RNA interference to knock downcomponents that promote tumor progression, and the tumor-targeted delivery of antitumoral double stranded RNA. Vectors appliedin GBM for the delivery of nucleic acids will be discussed. These include non-replicating and replicating (oncolytic) viruses, as well asnon-viral delivery vectors based on polycations or cationic lipids.
Therapeutic Strategies to Target Multiple Kinases in Glioblastoma by Sith Sathornsumetee (pp. 700-711).
Glioblastoma (GBM), the most common primary brain tumor in adults, is one of the most aggressive human cancersassociated with high mortality. Standard treatments following diagnosis include surgical resection, radiotherapy and adjunctive chemotherapy.However, almost all patients develop disease progression following this multimodal therapy. Recent understanding in genomicand molecular abnormalities in GBM has shifted the treatment paradigm towards using molecularly targeted agents. One of themost prominent targets in cancer treatment is kinases, which can be commonly targeted by small molecule inhibitors or monoclonalantibodies. Despite the initial enthusiasm in exploring kinase inhibitors for GBM, first-generation kinase inhibitors that selectivelydisrupt single kinases have failed to demonstrate clinical benefit in most patients with GBM. Mechanisms of resistance may includegenetic heterogeneity with cross-talk and coactivation of multiple signaling pathways, upregulation of alternative signaling cascades,limited drug delivery and existence of highly-resistant cellular subpopulations such as cancer stem cells. One strategy to circumvent thischallenge is to target multiple kinases by multitargeted kinase inhibitors or combinations of single targeted kinase inhibitors, both ofwhich have been evaluated in clinical trials for GBM.
Angiogenesis in Glioblastoma Multiforme: Navigating the Maze by Amanda G. Linkous, Eugenia M. Yazlovitskaya (pp. 712-718).
Blood vessel formation is a fundamental process that occurs during both normal and pathologic periods of tissue growth. Inaggressive malignancies such as glioblastoma multiforme (GBM), vascularization is often excessive and facilitates tumor progression. Inan attempt to maintain tumors in a state of quiescence, multiple anti-angiogenic agents have been developed. Although several angiogenesisinhibitors have produced enhanced clinical benefits in GBM, many of these pharmacologic agents result in transitory initialresponse phases followed by evasive tumor resistance. Thus, a significant need exists for the discovery of novel and effectiveanti-angiogenic therapies. The development of new molecular-targeted therapeutic strategies is often complicated by the complexityof angiogenic signal transduction. Due to the labyrinthine nature of these signaling pathways, increased production of other angiogenicfactors may compensate for the inhibition of key vascular targets like vascular endothelial growth factor (VEGF). Such compensatorymechanisms facilitate vascularization and allow tumor growth to proceed even in the presence of anti-angiogenic agents. This reviewpresents the challenges of targeting the intricate vascular network of GBM and discusses the clinical implications for recent advancementsin targeted anti-angiogenic drug therapy.
Targeting βIII-Tubulin in Glioblastoma Multiforme: From Cell Biology and Histopathology to Cancer Therapeutics by Christos D. Katsetos, Pavel Draber, Maria Kavallaris (pp. 719-728).
Glioblastoma multiforme (GBM) is the most common, aggressive, and chemorefractory brain tumor in human adults.Notwithstanding significant discoveries in the elucidation of pathways of molecular signaling and genetics of GBM during the past 20years there has been no breakthrough in the pharmacological treatment of this high-grade malignancy. We, and others, have previouslydemonstrated increased expression of βIII-tubulin in GBM asserting a link between aberrant expression of this β-tubulin isotype and adisruption of microtubule dynamics associated either with malignant tumor development de novo, or with progression and malignanttransformation of a low-grade glioma into GBM. This article reviews βIII-tubulin as a promising target in the experimental treatmentof GBM and examines the potential use of epothilones, a new family of anticancer agents shown to be active in βIII-tubulin-expressingtumor cells, as well as the “double hit” therapeutic concept of tumor cell sensitization to tubulin binding agents (TBAs) by III-tubulinsilencing. The latest progress regarding the function and potential role of βIII-tubulin in aggressive tumor behavior, cancer stem cells,tumor cell hypoxia, and resistance to taxane-related compounds, is also critically appraised.
Targeted Toxins for Glioblastoma Multiforme: Pre-Clinical Studies and Clinical Implementation by Marianela Candolfi, Kurt M. Kroeger, Weidong Xiong, Chunyan Liu, Mariana Puntel, Kader Yagiz, AKM Ghulam Muhammad, AKM Ghulam Muhammad, Yohei Mineharu, David Foulad, Mia Wibowo, Hikmat Assi, Gregory J. Baker, Pedro R. Lowenstein, Maria G. Castro (pp. 729-738).
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. GBM is very aggressive due to its poorcellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBM’s invasive natureas well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination ofhuman GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surroundingnon-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator(uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such asDiptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins forGBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients,efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in thetumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for localdelivery.
Clinical Development of Experimental Virus-Mediated Gene Therapy for Malignant Glioma by Nikolai G. Rainov, Volkmar Heidecke (pp. 739-747).
Advances in medical and surgical treatments in the last decades have resulted in quantum leaps in the overall survival ofpatients with many types of malignant disease, while survival of patients with malignant gliomas (WHO histological grades 3 and 4) hasbeen only moderately improved. Maximum surgical resection, external fractionated radiotherapy, and oral chemotherapy during and afterirradiation currently represent the pillars of malignant glioma therapy. Novel and experimental modalities aimed at a more selective andmore effective treatment are however being increasingly developed and tested in clinical studies.Improved understanding of the fundamental mechanisms of glioma growth, resistance, and recurrence has resulted in the introduction ofbiologically and molecularly targeted therapies such as virus-mediated gene therapy, often in combination with spatially defined deliverymethods specifically designed to be used in the local environment of the brain, such as convection-enhanced delivery.This review summarizes the key findings of the most important phase I and II clinical studies employing gene therapy with naturallyoccurring or genetically modified non-replicating or conditionally replicating (oncolytic) viruses, such as retrovirus, adenovirus,herpes-simplex-virus, Newcastle disease virus, or reovirus, in patients with primary or recurrent malignant gliomas. In addition, thetwo phase III gene therapy studies carried out to date in glioma patients and employing retrovirus or adenovirus vectors are presentedin detail and critically discussed. Areas of necessary improvements and possible future developments of viruses and delivery methodsare outlined.
Erlotinib in Glioblastoma - Lost in Translation? by Georg Karpel-Massler, M. Andrew Westhoff, Richard E. Kast, Christian Rainer Wirtz, Marc-Eric Halatsch (pp. 748-755).
Glioblastoma represents the most common primary brain tumor in adults. Despite improvements of multimodal therapy,the prognosis of this disease remains unfavorable. Thus, great efforts have been made to identify therapeutic agents directed againstthose specific molecular targets whose presence was shown to be associated with worse clinical outcomes. The epidermal growth factorreceptor (HER1/EGFR) has been identified as one such target, and different compounds were developed to inhibit HER1/EGFR and/or its mutant form, EGFRvIII. However, clinical trials did not confirm the initial enthusiasm conveyed by promising results fromexperimental studies. Therefore, a therapeutic approach directed at inhibiting solely HER1/EGFR does not seem to translate into aclinical benefit. This review discusses the current therapeutic situation in the setting of glioblastoma while putting the spotlight onerlotinib, a HER1/EGFR-targeted small molecule tyrosine kinase inhibitor.
The Rationale of Targeting Neutrophils with Dapsone during Glioblastoma Treatment by Richard E. Kast, Angelika Scheuerle, Christian R. Wirtz, Georg Karpel-Massler, Marc-Eric Halatsch (pp. 756-761).
Data from past research is presented showing that neutrophils are active participants in new vessel formation in normalphysiology, in proliferating human endometrium, in non-cancer pathologies as in the pannus of rheumatoid arthritis, and in variouscancers, among them glioblastoma. These data show that interleukin-8 (IL-8) is a major chemokine attracting neutrophil infiltratesin these states. Since the old anti-Hansen's disease drug dapsone inhibits neutrophil migration along an IL-8 gradient towardsincreasing concentrations, and is used therapeutically for this attribute to good effect in dermatitis herpetiformis, bullous pemphigoid andrheumatoid arthritis, we suggest dapsone may deprive glioblastoma of neutrophil-mediated growth promoting effects. We review pastresearch showing that vascular endothelial growth factor, VEGF, is carried predominantly intracellularly within neutrophils- only 2% ofcirculating VEGF is found free in serum. Based on the available evidence summarized by the authors, dapsone has a strong theoreticalpotential to become a useful anti-VEGF, anti-angiogenic agent in glioblastoma treatment.
Effect of Selenium-Saturated Bovine Lactoferrin (Se-bLF) on Antioxidant Enzyme Activities in Human Gut Epithelial Cells Under Oxidative Stress by Hannah Burrow, Rupinder K. Kanwar, Ganesh Mahidhara, Jagat R. Kanwar (pp. 762-771).
Cancer and many chronic inflammatory diseases are associated with increased amounts of reactive oxygen species (ROS). Thepotential cellular and tissue damage created by ROS has significant impact on many disease and cancer states and natural therapeutics arebecoming essential in regulating altered redox states. We have shown recently that iron content is a critical determinant in the antitumouractivity of bovine milk lactoferrin (bLF). We found that 100% iron-saturated bLF (Fe-bLF) acts as a potent natural adjuvant andfortifying agent for augmenting cancer chemotherapy and thus has a broad utility in the treatment of cancer. Furthermore, we also studiedthe effects of iron saturated bLF’s ability as an antioxidant in the human epithelial colon cancer cell line HT29, giving insights into thepotential of bLF in its different states. Thus, metal saturated bLF could be implemented as anti-cancer neutraceutical. In this regard, wehave recently been able to prepare a selenium (Se) saturated form of bLF, being up to 98% saturated. Therefore, the objectives of thisstudy were to determine how oxidative stress induced by hydrogen peroxide (H2O2) alters antioxidant enzyme activity within HT29epithelial colon cancer cells, and observe changes in this activity by treatments with different antioxidants ascorbic acid (AA), Apo (ironfree)-bLF and selenium (Se)-bLF. The states of all antioxidant enzymes (glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s-transferase (GsT), catalase and superoxide dismutase (SOD)) demonstrated high levels within untreated HT29 cells comparedto the majority of other treatments being used, even prior to H2O2 exposure. All enzymes showed significant alterations in activity whencells were treated with antioxidants AA, Apo-bLF or Se-bLF, with and/or without H2O2 exposure. Obvious indications that the Se contentof the bLF potentially interacted with the glutathione (GSH)/GPx/GR/GsT associated redox system could be observed immediately,showing capability of Se-bLF being highly beneficial in helping to maintain a balance between the oxidant/antioxidant systems withincells and tissues, especially in selenium deficient systems. In conclusion, the antioxidative defence activity of Se-bLf, investigated in thisstudy for the first time, shows dynamic adaptations that may allow for essential protection from the imbalanced oxidative conditions. Becauseof its lack of toxicity and the availability of both selenium and bLF in whole milk, Se-bLF offers a promise for a prospective naturaldietary supplement, in addition to being an immune system enhancement, or a potential chemopreventive agent for cancers.
Update on Laser Photochemotherapy: An Alternative for Cancer Treatment# by Marcos B. Paiva, Jayne Joo, Marcio Abrahao, Joao Carlos Ribeiro, Onivaldo. Cervantes, Joel A. Sercarz (pp. 772-779).
Although major progress has been made in surgery, radiation, and chemotherapy for the treatment of malignancy during thelast 20 years, there has been little improvement in the survival of patients with recurrent or advanced head and neck cancer. Because ofthe ease and accessibility for surgery and their loco-regional biological behavior, head and neck cancers serve as an ideal model to testcombined laser energy delivered via interstitial fiberoptics and chemotherapeutic agents activated by photo-thermal energy as an alternative,less invasive treatment for cancer. A number of investigators have shown that anthracyclines and cisplatin are likely candidates forlight or heat activation in cancer cells. Maximum tolerated dose followed by photochemical and thermal activation via laser fiberopticscan improve treatment by sensitizing tumor response. The higher intratumor drug levels compared to systemic drug administration alongwith laser activation should also reduce systemic toxicity. In this article the authors analyze the concept of combining anti-cancer drugsand laser therapy and review the clinical application. In summary, the literature available suggests photochemotherapy with currentlyapproved drugs and lasers may soon become an attractive alternative for cancer treatment.