Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
This chapter describes the various families of DNA-interactive agents categorized according to their mechanism of action. Dacarbazine, procarbazine, and temozolomide are known as methylating agents because they work by methylating guanine bases within the major groove of DNA, predominantly at the O6-position. Although dacarbazine and procarbazine are relatively toxic and now have limited use, temozolomide is used extensively for glioma, and increasingly for melanoma. Some of the more well-known analogs, nedaplatin, satraplatin, picoplatin, and triplatin tetranitrate, are described below. Mixed-base backbone-modified nucleic acids can undergo perfect base-pair recognition when binding to DNA or RNA, and often have enhanced binding affinity and sequence specificity. Synthetic peptide nucleic acid oligomers such as PNA are designed to bond to RNA via standard Watson-Crick base pairing in a sequence-selective fashion, preventing its translation into the corresponding protein. Based on this concept, some researchers are now designing some small molecules specifically targeted at transcription factor binding sites.
Neoplasms
Ad (Sandy) Macleod, Ian Maddocks in The Psychiatry of Palliative Medicine, 2018
The common tumours within the nervous system, gliomas and cerebral metastases, are rarely curable. The most common primary brain tumour is glioblastoma multiforme. The terminal management of malignant tumours affecting the nervous system is challenging. The journey from acute presentation to death can be agonising. Evaluating the benefit–risk ratio in the management of neoplasms is critically important. The benefits of debulking surgery, radiotherapy and chemotherapy require balancing against the adverse effects of these relatively crude interventions. The propensity to develop sustained and troublesome anxiety, often precipitated by situations, is enhanced in those with brain tumours. The situation with depression is similar, the risk being enhanced by the multiple losses accumulated during the illness. Anxious irritability, rather than overt misery of mood, is not unusual in organic conditions. Both anxiety and depression are more likely early in the course of illness when insight and judgement is retained and the devastating impact on life is able to be acknowledged.
Glioblastoma
Dongyou Liu in Tumors and Cancers, 2017
Glioblastoma (formerly glioblastoma multiforme), a WHO Grade IV tumor, represents the most common primary malignant brain tumor, with extremely aggressive behavior. It can arise de novo or result from malignant transformation of other gliomas, such as diffuse astrocytoma and/or anaplastic astrocytoma. Glioblastoma exhibits the highest degree of angiogenesis of all solid tumors. Patients with glioblastoma often manifest with the classical triad of increased intracranial pressure. Characteristic histopathological features of glioblastoma include nuclear atypia, mitotic activity, microvascular proliferation, and necrosis. The current standard care for glioblastoma consists of safe maximal surgical resection followed by concurrent radiation followed by adjuvant temozolomide. The prognosis of glioblastoma remains poor despite advancements in treatment. Younger age at diagnosis and good performance status are independent favorable prognostic factors. Glioblastoma exhibits heterogeneity at the morphological, biological, genomic, and antigenic levels, rendering the tumor cells resistant to available treatment modalities.
Challenges in the development of a survivin vaccine (SurVaxM) for malignant glioma
Published in Expert Review of Vaccines, 2014
Robert A Fenstermaker, Michael J Ciesielski
There is growing interest in immunotherapy for malignant gliomas. This interest stems from a number of immunological observations, together with the failure of conventional therapeutic agents to produce broad and clinically meaningful improvements in survival and quality of life. The challenges faced in translating laboratory-based immunological observations to Phase I and II clinical trials for immunotherapy of gliomas are substantial. Nevertheless, as our understanding of the effects of active specific vaccination in glioma patients grows, results support optimism that such methods may eventually prove useful as an adjunctive treatment for these cancers. This paper highlights a number of barriers encountered in the translational development of a survivin-targeted peptide vaccine (SurVaxM) for patients with malignant gliomas.
Ephs and Ephrins in malignant gliomas
Published in Growth Factors, 2014
Sara Ferluga, Waldemar Debinski
Eph receptor tyrosine kinases and the corresponding ephrin ligands play a pivotal role in the glioma development and progression. Aberrant protein expression levels of the Eph receptors and ephrins are often associated with higher tumor grade and poor prognosis. Their function in tumorigenesis is complex due to the intricate network of possible co-occurring interactions between neighboring tumor cells and tumor microenvironment. Both Ephs and ephrins localize on the surface of tumor cells, tumor vasculature, glioma stem cells, tumor cells infiltrating brain, and immune cells infiltrating tumors. They can both promote and inhibit tumorigenicity depending on the downstream forward and reverse signalling generated. All the above-mentioned features make the Ephs/ephrins system an intriguing candidate for the development of new therapeutic strategies in glioma treatment. This review will give a general overview on the structure and the function of Ephs and ephrins, with a particular emphasis on the state of the knowledge of their role in malignant gliomas.
Current and emerging molecular targets in glioma
Published in Expert Review of Anticancer Therapy, 2010
Rafael Roesler, André T Brunetto, Ana Lucia Abujamra, Caroline Brunetto de Farias, Algemir Lunardi Brunetto, Gilberto Schwartsmann
Gliomas are the most common and lethal neurological cancers. Despite research efforts, the prognosis for patients with malignant gliomas remains poor. Advances in the understanding of cellular and molecular alterations in gliomas have led to the emergence of experimental molecularly targeted therapies. This article summarizes recent progress in the development of targeted therapies for glioma, focusing on emerging molecular targets, including neuropeptide and neurotrophin pathways, glutamate receptors, epigenetic mechanisms and glioma stem cell targets. Recent clinical trials of small molecules and antibodies targeted at growth factor pathways and intracellular signaling cascades are also discussed.
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