Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines

BCRP/ABCG2 emerged as an important multidrug resistance protein, because it confers resistance to several classes of cancer chemotherapeutic agents and to a number of novel molecularly-targeted therapeutics such as tyrosine kinase inhibitors. Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor used in the treatment of patients with advanced non small cell lung cancer (NSCLC) carrying activating EGFR mutations. Membrane transporters may affect the distribution and accumulation of gefitinib in tumour cells; in particular a reduced intracellular level of the drug may result from poor uptake, enhanced efflux or increased metabolism

<i>ABCB1</i> (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells

BACKGROUND: Clinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of routinely prescribed chemotherapy drugs are poorly understood. METHODS: We created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells±the ABCB1 inhibitors verapamil and elacridar and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461. ABCB1 expression was assessed by qRT-PCR, copy number, western blotting and immunohistochemical analysis and ABCB1 activity assessed by the Vybrant and P-glycoprotein-Glo assays. RESULTS: Paclitaxel-resistant cells were cross-resistant to olaparib, doxorubicin and rucaparib but not to veliparib or AZD2461. Resistance correlated with increased ABCB1 expression and was reversible following treatment with the ABCB1 inhibitors verapamil and elacridar. Active efflux of paclitaxel, olaparib, doxorubicin and rucaparib was confirmed in drug-resistant cells and in ABCB1-expressing bacterial membranes. CONCLUSIONS: We describe a common ABCB1-mediated mechanism of paclitaxel and olaparib resistance in ovarian cancer cells. Optimal choice of PARP inhibitor may therefore limit the progression of drug-resistant disease, while routine prescription of first-line paclitaxel may significantly limit subsequent chemotherapy options in ovarian cancer patients

Cancer stem cell metabolism: A potential target for cancer therapy

© 2016 The Author(s). Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have gained intense interest as key tumour initiating cells that may also play an integral role in tumour recurrence following chemotherapy. Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic and biosynthetic requirements. They are largely dependent on aerobic glycolysis for their energy production and also are associated with increased fatty acid synthesis and increased rates of glutamine utilisation. Emerging evidence has shown that therapeutic resistance to cancer treatment may arise due to dysregulation in glucose metabolism, fatty acid synthesis, and glutaminolysis. To propagate their lethal effects and maintain survival, tumour cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation. It is now evident that cancer cells metabolise glutamine to grow rapidly because it provides the metabolic stimulus for required energy and precursors for synthesis of proteins, lipids, and nucleic acids. It can also regulate the activities of some of the signalling pathways that control the proliferation of cancer cells. This review describes the key metabolic pathways required by CSCs to maintain a survival advantage and highlights how a combined approach of targeting cellular metabolism in conjunction with the use of chemotherapeutic drugs may provide a promising strategy to overcome therapeutic resistance and therefore aid in cancer therapy

Impact of a Pharmacist-Driven Protocol to Improve Drug Allergy Documentation at a University Hospital

BACKGROUND: An internal evaluation of the inpatient pharmacy order entry database (WORx) at a university hospital revealed that the nature of the reaction was documented for only 47% of patients with reported drug allergies/intolerance. Insufficient documentation of drug allergy/intolerance may result in administration of drugs that should not be prescribed. Similarly, valuable agents that should be used may not be prescribed due to an unnecessary fear of adverse drug reaction. More complete description of drug allergy/intolerance may result in more correct prescribing of medications. OBJECTIVE: Evaluate the impact of a pharmacist-driven protocol on the quality of drug allergy/intolerance documentation. METHODS: Four pre-intervention evaluations were conducted every 2 weeks documenting the completeness of drug allergy/intolerance information in the pharmacy order entry database. One week following the implementation of a pharmacist-driven protocol intended to improve the completeness of drug allergy/intolerance information, a series of 4 postintervention evaluations was repeated. Proportional analysis of pre- and postinterventional data was performed to evaluate the effectiveness of the intervention. RESULTS: A total of 1,686 allergies from 2,174 patients were reviewed pre and post intervention. The frequency of complete drug allergy/intolerance documentation pre intervention was 52% to 62%. Following implementation of the hospitalwide, pharmacist-driven protocol, this rate increased to 60% to 76%. Pediatric services demonstrated the most substantial improvement, increasing from 53% to 79% to 67% to 93%. Blank reaction fields decreased by 10% in both age groups. CONCLUSION: A pharmacy-driven initiative intended to improve the completeness of drug allergy/intolerance documentation was associated with modest success. Other mechanisms, including electronic health record systems with computerized physician order entry and decision support, are needed to improve the completeness of drug allergy/intolerance information