Anti-cancer agents in medicinal chemistry
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Anticancer Agents Med Chem · Oct 2011
ReviewAngiogenesis in glioblastoma multiforme: navigating the maze.
Blood vessel formation is a fundamental process that occurs during both normal and pathologic periods of tissue growth. In aggressive malignancies such as glioblastoma multiforme (GBM), vascularization is often excessive and facilitates tumor progression. In an attempt to maintain tumors in a state of quiescence, multiple anti-angiogenic agents have been developed. ⋯ Due to the labyrinthine nature of these signaling pathways, increased production of other angiogenic factors may compensate for the inhibition of key vascular targets like vascular endothelial growth factor (VEGF). Such compensatory mechanisms facilitate vascularization and allow tumor growth to proceed even in the presence of anti-angiogenic agents. This review presents the challenges of targeting the intricate vascular network of GBM and discusses the clinical implications for recent advancements in targeted anti-angiogenic drug therapy.
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Anticancer Agents Med Chem · Jul 2011
ReviewTherapeutic potential of targeting glypican-3 in hepatocellular carcinoma.
Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. ⋯ The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker.
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Anticancer Agents Med Chem · Jan 2011
ReviewRegulatory cascades of protein phosphatases: implications for cancer treatment.
Coordinated coupling of biochemical reactions involving protein phosphorylation and dephosphorylation represents the hallmark of the intracellular signal transduction machinery. Distinct classes of enzymes known as kinases and phosphatases respectively drive these reactions. Alterations in activity of such signaling intermediates, either due to mutations in the corresponding genes or epigenetic modulation of their expression levels, is often the cause of many cancers. ⋯ The crosstalk between such regulatory axes of phosphatases and kinase cascades provides for complex modes of regulation, with non-linear signal input/output relationships. This review discusses the implications of such phosphatase-constituted regulatory elements for both signal processing and transmission. Further, we also explore the potential that insights on the functioning of phosphatase cascades offers, for the development of new and selective strategies for cancer therapy.
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Anticancer Agents Med Chem · Jan 2011
ReviewProtein phosphatase 2A as a potential target for anticancer therapy.
The kinase oncogenes are well-characterized drivers of cancer development, and several targeted therapies focused on both specific and selectively nonselective kinase inhibitors have now been approved for clinical use. In contrast, much less is known about the role of protein phosphatases, although modulation of their activities might form the foundation for an effective anti-cancer approach. ⋯ Recently pharmacological modulation of PP2A activity has been showed to have a potent anti-tumor activity in both in vitro and in vivo cancer models. These studies implicate PP2A as a promising therapeutic target for the treatment of cancer.
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Anticancer Agents Med Chem · Sep 2010
ReviewOvercoming resistance of glioblastoma to conventional cytotoxic therapies by the addition of PARP inhibitors.
This article will present the rationale for combining chemical inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) with conventional cytotoxic agents to improve the treatment of glioblastoma. After a brief review of the current therapeutic options for these aggressive tumours, the possible reasons for their resistance to radiation and chemotherapy will be discussed, highlighting the important role of DNA damage response pathways in many key resistance mechanisms. The dose-limiting toxicities associated with radiation and chemotherapy treatment will be described in order to illustrate the importance of tumour specificity in any attempt to increase the effectiveness of conventional treatments. ⋯ After a brief summary of the key DNA damage response pathways, the biology, biochemistry and pharmacology of PARP and the existing PARP inhibitors will be presented. The major part of the review will cover the effects of combining PARP inhibitors with radiation and chemotherapy in vitro and in vivo, commenting on the underlying mechanisms and indicating where the data are predictive of tumour specific sensitization. Finally, we will consider specific scenarios where PARP inhibitors might contribute to the treatment of glioblastoma patients, discuss the challenges and opportunities associated with early phase clinical testing of these agents, and describe the clinical trials that are either underway or in development.