SUMMARYWhat is known and objective: The off-label use of medicines is widespread in several diseases. This type of prescribing practice is particularly more acute in oncology. However, the suitability of anticancer medications for off-label use remains an issue of controversy, due to uncertainty around the clinical benefits and potential toxicities, limited evidence to support clinical decisionmaking, increased out-of-pocket costs for patients and ethical concerns around the lack of informed consent. Currently, data pertaining to the global prevalence of off-label use in cancer therapy are lacking. The aim of this review was to provide an overview of off-label drug use prevalence in oncology. Methods: A systematic literature search was performed in PubMed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines from 1975 to 2016. Studies assessing the prevalence of off-label use of anticancer drugs were included. Data synthesis: Of the 199 eligible papers retrieved, 23 studies were included in this systematic literature review. Off-label drug use in inpatients ranged from 18% to 41%. Among adult patients with cancer, 13%-71% received a minimum of one offlabel chemotherapy. The main reasons for off-label drug use were 'drug unapproved for specific tumour' and 'modified drug applications'. Among adults, metastatic cancers and palliative care patients received the most off-label drugs. The off-label drug use unsupported by standard treatment guidelines or drug compendia was in the range of 7%-31%. Conclusion: Off-label drug use in cancer therapy is commonly practised but outcomes could vary significantly. Hence, greater scrutiny and robust clinical guidance is needed to establish the favourable benefit-risk ratio for patients at the time of prescribing at each level of oncology care to facilitate rational off-label prescribing. WHAT IS KNOWN AND OBJECTIVEOff-label drug use refers to prescribing medicines in a manner that is inconsistent with prescribing information published by regulatory authorities. Off-label drug use can be classified into different categories, such as unapproved indication, use in a special population, through an unapproved route of administration or with a dose not specified in the FDA-approved label.1 Off-label drug use based on little or no scientific evidence is termed as off- 3 Off-label drug use is further differentiated from unlicensed drug use, which refers to the use of a therapeutic entity which has never received any regulatory approval for clinical use in either paediatrics or adult population (Table 1).1 Off-label prescribing is prevalent across different diseases and healthcare settings; however, it is more frequently reported in paediatrics, psychiatry and oncology. [4][5][6] Physicians are generally allowed to prescribe the drug in an offlabel manner in most regions in the world except in countries such as India where it is illegal. 7 The off-label status of a drug could also vary among different countries due to different marketing authorization ...

The mechanistic target of rapamycin (mTOR), via its two distinct multiprotein complexes, mTORC1, and mTORC2, plays a central role in the regulation of cellular growth, metabolism, and migration. A dysregulation of the mTOR pathway has in turn been implicated in several pathological conditions including insulin resistance and cancer. Overactivation of mTORC1 and disruption of mTORC2 function have been reported to induce insulin resistance. On the other hand, aberrant mTORC1 and mTORC2 signaling via either genetic alterations or increased expression of proteins regulating mTOR and its downstream targets have contributed to cancer development. These underlined the attractiveness of mTOR as a therapeutic target to overcome both insulin resistance and cancer. This review summarizes the evidence supporting the notion of intermittent, low dose rapamycin for treating insulin resistance. It further highlights recent data on the continuous use of high dose rapamycin analogs and related second generation mTOR inhibitors for cancer eradication, for overcoming chemoresistance and for tumor stem cell suppression. Within these contexts, the potential challenges associated with the use of mTOR inhibitors are also discussed.

No abstract

Nimbolide is one of the main components in the leaf extract of Azadirachta indica (A. indica). Accumulating evidence from various in vitro and in vivo studies indicates that nimbolide possesses potent anticancer activity against several types of cancer and also shows potential chemopreventive activity in animal models. The main mechanisms of action of nimbolide include anti-proliferation, induction of apoptosis, inhibition of metastasis and angiogenesis, and modulation of carcinogen-metabolizing enzymes. Although multiple pharmacodynamic (PD) studies have been carried out, nimbolide is still at the infant stage in the drug development pipeline due to the lack of systematic pharmacokinetic (PK) studies and long-term toxicological studies. Preclinical PK and toxicological studies are vital in determining the dosage range to support the safety of nimbolide for first-in-human clinical trials. In this review, we will provide a comprehensive summary for the current status of nimbolide as an anticancer and chemopreventive lead compound, and highlight the importance of systematic preclinical PK and toxicological studies in accelerating the process of application of nimbolide as a therapeutic agent against various malignancies.

No abstract