| Description |
Opioid receptor agonism has been shown to promote resistance to, or synergism with, conventional chemotherapeutics that are dependent upon malignant cell type. Pharmacodynamic interactions between newer molecularly targeted chemotherapeutic agents, such as tyrosine kinase inhibitors (TKIs), and opioids remain unknown. TKIs have become the standard of care for many diseases, including cancers driven by constitutively active tyrosine kinases. Imatinib mesylate and dasatinib are FDA approved TKIs for the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemias. The mu opioid receptor (MOP) agonists, morphine and fentanyl, are routinely used in the management of cancer and cancer-treatment-related pain. My study evaluates the consequences of MOP agonism on tyrosine kinase activity in the context of Ph+ CML cells. I hypothesize a synergistic effect between TKIs and opioids in K562 cells, an immortalized human erythroleukemia cell line, will be observed. My approach uses a high-throughput assay to treat a well-characterized Ph+ CML cell line with a MOP agonist (morphine and fentanyl) either concomitantly or with a 24-hour pre-incubation, followed by treatment with TKI (imatinib or dasatinib). Anti-cancer effects of dasatinib at IC10, IC50, and IC90 levels were antagonized by the presence of MOP agonism in a dose-dependent manner. Antagonism on dasatinib efficacy in the presence of MOP agonists warrants additional studies to evaluate drug- iv drug interactions between opioids as well as supportive care therapies and their effects on TKIs utilized in leukemic patients. TKI therapies are often administered for life, adding an increased urgency to understand drug-drug interactions that may exist and effect remission duration. |
