Clinical Cancer Drugs - Volume 4, Issue 1, 2017

Background: In recent times, miRNA has been able to catch the significant attention of scientists worldwide. This small part of non-coding RNA has finally been recognized for its enormous potential for cleavage, m-RNA degradation, and translational modifications. Moreover, miRNA has now been included in the list of quite important class of blood based biomarkers, which shows their specific signatures as circulating microRNA in various diseases like cancer, hypertrophy, Parkinson's, Alzheimer's disease, etc. Keeping in view of the enormous potential of miRNA, computational bioinformatics approaches have now been explored in detail, which has resulted not only in a large number of databases of the same, but also in the programs delivering information about their structural and functional relevance, using OMICS approaches. Objective: This review has an aim of discussing the significant details of microRNA, their function as targets for various diseases like cancer, related databases and associated biological applications. Method: An extensive literature survey was performed on miRNAs, its relevant databases, which are used for the search of their structure and function, miRNA biogenesis pathway and a range of miRNAs involved in various diseases, in particular cancer. Results: Using OMICS approaches and innovative techniques, the structural and biological roles of miRNA in relation to various diseases has now been established. Role of miRNAs as biomarkers, its applications in various cellular processes, its function as a target of certain diseases are now some of the quite common patterns of studies. Conclusion: With an update on relevant aspects, the regulatory and functional roles of miRNA would be elucidated for providing future insights into the unmapped cellular mechanisms of life processes, which may further facilitate our understanding about various challenging diseases.

Objective: Emergence of nitrogen mustards and their derivatives as DNA alkylating agent and their expanding anti-cancer applicability did fuel up massive efforts directed towards the design of anticancer agents in clinical practice. Considerable progress in this field has been achieved in the last few decades. Rich panoply of literature has illustrated the rather underexploited or completely novel therapeutic approaches based on these compounds and biological targets which are of special interest. The prime objective of the present article is to highlight a majority of the landmark efforts been devoted into the understanding of nitrogen mustards as DNA alkylator and focuses on nitrogen mustards; their discovery, mechanism of action and their derivatives synthesized so far. Results: Alkylation of DNA is held primarily responsible for cell death. DNA alkylators covalently bind with DNA thereby inhibiting its natural processes and thus cause cell deaths. Various DNA alkyators, aziridines, epoxides, methane sulfonates, nitrosoureas, methyl hydrazines, platinum complexes and most prominently nitrogen mustards and its derivatives are extensively studied. Alkylation by nitrogen mustards proceeds via the formation of aziridinium ion intermediate adopting SN1 or SN2 pathway depending on the type of alkylating drugs. Ab-initio studies on isolated GC base pairs have confirmed that nitrogen mustard derivative like chlorambucil attacks preferentially the N7 position of guanine. Also alkylation by nitrogen or sulphur mustards is enthalpy driven (ΔH < 0) and spontaneous (ΔG < 0). Conjugation of melphalan, chlorambucil and other nitrogen mustards to steroids, as well as conjugation of CNS active chromophore to nitrogen mustards have led to designing new potent anti-cancer drugs. Conclusion: The article extensively dwells in studies (both experimental and theoretical) on different DNA interacting drugs, types of DNA alkylators focussing particularly on nitrogen mustards and fate of alkylated DNA. Drug resistance and site specificity have been the major impediment in devising nitrogen mustard based cancer therapy. Among several nitrogen mustard derivatives synthesized, tallimustine, distamycine have been among the particularly successful derivatives in overcoming these limitations. Future studies on designing cell specific anti cancer drugs based on nitrogen mustards are deemed essential.

Background: With 23% of all new tumour cases, breast cancer is the most common cancer among women worldwide, and is the second leading cause of cancer deaths in women after lung cancer. Of more than one million cases of breast cancer diagnosed globally each year, a high percentage is characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with triple-negative breast cancer. The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR-pathway plays a critical role in malignant transformation of human tumours and their subsequent growth, proliferation and metastasis. Therefore, this pathway is regarded as an attractive candidate for therapeutic interventions. Several inhibitors targeting different components of this pathway are in various stages of development. This review provides a short overview of the PI3K/AKT/mTOR-signalling network, discusses the rationale for targeting this pathway and summarizes the use of the PI3K/AKT/mTOR-pathway as drug target for triple-negative breast cancer treatment. Conclusion: Drugs interacting with the PI3K/AKT/mTOR-pathway seems to be an attractive therapeutic option in triple-negative breast cancer.

Background: Cisplatin is a commonly used anti-cancer drug. However, its use is associated with severe side effects including ototoxicity that affects a large fraction of cisplatin-treated patients. Approved therapies that reduce cisplatin-induced ototoxicity are lacking. Among the candidate therapeutics, dexamethasone stands out. There is extensive experience of its use in combination with cisplatin for the prevention of chemotherapy-induced nausea and vomiting indicating that dexamethasone does not affect the anti-cancer effects of cisplatin. Objective: The objective of this study is to assess the potential of dexamethasone for the prevention of cisplatin-induced ototoxicity by a systematic analysis of the available evidence. Method: The databases PubMed and Web of Science were used to identify relevant articles by using the search terms 'cisplatin', 'ototoxicity', and 'dexamethasone'. Results: We identified 16 relevant original research articles. The analyzed studies reported conflicting results on the effects of dexamethasone on cisplatin-induced ototoxicity. However, studies in which dexamethasone was used prior to cisplatin treatment and directly administered into the tympanic cavity of the middle ear consistently reported beneficial effects. The use of sustained release formulations that prolong the availability of dexamethasone within the ear further improved the efficacy of dexamethasone. Conclusion: Dexamethasone is a promising candidate drug for the prevention of cisplatin-induced ototoxicity when applied intratympanically. Optimized formulations and administration schedules with regard to dose and time of application need to be developed.

Background: Brain tumors often go unnoticed in psychiatry population. Often the tumors remain silent before they present as behavioral changes or neurological signs. Brain tumors often present with psychiatric symptoms such as mood changes (depression or mania), psychotic symptoms, panic attacks, and changes in personality, or memory difficulties. The mengiomas of brain are often silent because of their slow growth. Methods: We present a case of an elderly female who presented with psychotic symptoms and gait disturbances. On evaluation she was diagnosed as a case of frontal meningioma. A case study was prepared and analyzed and a brief review of literature was done using keywords neuropsychiatric aspects of brain tumours, meningioma and psychosis. Results and Conclusions: There is a need to assess in detail elderly patients who present with psychiatric symptoms in an old age and neuroimaging must be done when patient presents with psychiatric symptoms and specific CNS signs.

Background: To evaluate the prevalence of peripheral neuropathy associated with bortezomib and its relation to multiple myeloma versus other malignancies. Methods: This is a retrospective chart review study. Subjects who received bortezomib at HealthEast Care System for various malignancies were evaluated. Statistical analyses were performed using SAS Enterprise Guide software version 5.1. All comparison data were analyzed using Pearson's Chi-Square. Results: A total of 64 patients received bortezomib for various cancer and blood disorders. Two patients were excluded from the analysis; one patient was diagnosed to have the possible POEMS syndrome and another patient developed neuropathy after receiving multiple chemotherapy agents. Bortezomib related neuropathy was seen in 46.8% (29 out of 62) of study patients. Neuropathy was higher in patients with multiple myeloma (41.9%) vs. non-multiple myeloma (4.8%) with a p-value of 0.0091. The development of peripheral neuropathy has no relation to age, gender, and prior neuropathy. Neuropathy developed in 75.9% of patients within four cycles of treatment (p=0.005). Conclusion: Peripheral neuropathy is more common in multiple myeloma patients who received bortezomib when compared with non multiple myeloma patients and develops in the first four cycles of treatment.