Inhibitor Medication Research Articles

Autophagic, apoptotic, and necrotic cancer cell fates triggered by acidic pH microenvironment.

Cancer as a multifactorial and smart disease is now considered a challenging problem. Despite many investigations on drug discovery, it remains incurable, in part, due to insufficient understanding of its special mechanisms. For the first time, we collaterally investigated the effect of acidosis on the contribution of apoptosis, necrosis, and autophagy in MDA-MB 231 cells. Our data showed that necrosis, apoptosis, and intracellular reactive oxygen species production drastically decreased from 48 to 72 hr while cell viability and autophagy increased along with a gap between the percentages. Eventually, the decrease of necrosis and apoptosis was related to upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and fatty acid synthetase, respectively. It seems that at the early stage of cancer progression, apoptosis is the main mechanism of cell mortality and afterward autophagy would be the main mechanism of cell survival. Therefore, at the acute phase of cancer, apoptotic inducer medications would be effective while at the chronic phase of cancer progression, autophagy inhibitor medication would be added as well. This eventually means that autophagy acts as both cell death and survival mechanisms at the onset of cancer progression with the approach towards cell survival. Besides other unknown cell survival mechanisms are involved in cell viability, except for apoptosis and necrosis inhibition and autophagy improvement. This study reiterates the inefficaciousness of autophagy inhibitor's medication at the onset of disease. It also emphasizes discovering other cell death mechanisms for cancer cell adaptation at the onset of disease with the aim of their targeting in cancer invasion therapy.

Developing a standard approach to immune checkpoint inhibitor toxicity management in Ontario.

255 Background: The use of immune checkpoint inhibitor medications (ICIs) in the province of Ontario, Canada has increased in volume by almost 4 fold between 2015/16 to 2017/18 and has expanded from use primarily in melanoma to lung, genitourinary, and other cancers. Lack of widespread clinical experience with ICIs and provincial variation in the management of the potentially life-threatening immune-related adverse effects (irAEs) was identified as a safety and quality gap. Cancer Care Ontario (CCO) set out to develop user-friendly health care provider and patient resources to facilitate a standard approach to ICI toxicity management in Ontario. Methods: A multidisciplinary working group of oncology clinicians with ICI experience reviewed available literature and current approaches to ICI toxicity management. An iterative consensus-building process was used to develop a practical guideline. This was circulated to an external expert review panel for content validity. Complementary patient/caregiver information was created based on best practices in health literacy and input from patient and family advisors. All resources were made publicly available via the CCO website and disseminated broadly to relevant stakeholders. Results: A user-friendly clinical practice guideline was created. It contains a description of irAEs associated with ICIs, guidance on the general management of irAEs, detailed algorithms describing the assessment and management of ten specific irAEs, and general considerations for patients on ICIs. A toolkit was developed with direct links to the algorithms, a customizable wallet card, a “Dear Healthcare Professional” letter template, and a patient information sheet. The guideline and toolkit webpages were accessed over 1500 times in the first month, suggesting that broad dissemination has been successful. Informal reports of guideline implementation were received from several Ontario hospitals. Conclusions: Careful analysis of the available literature and application of oncology professionals’ expertise resulted in evidence-informed, consensus-based practical resources to help facilitate safe, standardized ICI toxicity management across the Ontario health care system.