United States: On Wednesday, August 30, 2023, new data analysis published in the Clinical Cancer Research journal indicates a potential association between the use of lorazepam (marketed as Ativan) and unfavorable survival outcomes in pancreatic cancer patients. Researchers found that individuals with pancreatic cancer who were prescribed lorazepam faced a 3.83-fold higher likelihood of cancer recurrence compared to those not taking the drug. Conversely, patients taking alprazolam experienced a reduced risk of disease progression or mortality.

This investigation was initiated by examining historical data encompassing survival outcomes and prescription records of pancreatic cancer patients who received chemotherapy between 2004 and 2020 at the Roswell Park Comprehensive Cancer Center. The study involved 40 patients who had been prescribed lorazepam, 29 who had not, 27 taking alprazolam, and 42 without alprazolam.

To delve deeper into the potential mechanism behind these findings, researchers conducted experiments using a mouse model of pancreatic cancer. Their results indicated that the introduction of lorazepam altered the tumor microenvironment in a manner that typically induces chemotherapy resistance.

While previous research had hinted at a link between benzodiazepines (BZDs) and varying patient outcomes, this study is one of the first to investigate their potential impact on the tumor microenvironment.

The research team's hypothesis pointed towards the involvement of a G-protein coupled receptor known as GPR68. GPR68 is commonly expressed on fibroblast cells within the tumor microenvironment. Activation of GPR68 was found to increase the expression of the cytokine IL-6, leading to inflammation in the microenvironment, which has been linked to tumor progression.

The differentiation between lorazepam and alprazolam's effects on GPR68 was attributed to their chemical structures. Lorazepam belongs to the N-unsubstituted BZD class, which can activate GPR68, while alprazolam, an N-substituted BZD, cannot. This difference stems from the presence of a nitrogen atom, with N-substituted BZDs forming three bonds with non-hydrogen atoms, as opposed to N-unsubstituted BZDs, such as lorazepam, where the same nitrogen forms at least one bond with hydrogen.

Mary Mader, a medicinal chemist at the Indiana Biosciences Research Institute, explained that the subtle difference in chemical structure, such as the substitution of an N-H with N-CH3 and the replacement of N-H and C=O with an entire triazole ring in alprazolam, could account for this selectivity.