Flashcards in mTOR Inhibitors Deck (7)
What are the two mTOR inhibitors?
What are there 3 MOA?
1. Reducing cell growth and proliferation
2. Prevention of angiogenesis
3. Synergy with drugs that damage DNA
What does reducing cell growth and proliferation do to the cancer cell?
1. Decreased cell cycle progression
-mTOR regulates protein synthesis of cyclin D1, which controls progression through the G1/S checkpoint
---Important when cyclin D1 is overexpressed (e.g. mantle cell lymphoma)
2. Reduced bioenergetics
-Cancer cells rely on glycolysis to provide ATP
-mTOR increases expression of amino acid and glucose transporters, which are unregulated in several cancers
---> mTOR inhibition decreases access to nutrient and metabolic fuel
What does preventing angiogenesis do to the cancer cell?
-Decreasing synthesis and release of angiogenic growth factors (esp. VEGF and PDGF) from the cancer cells
-Blocking growth and proliferation of vascular cells
What does synergy with drugs that damage DNA do to cancer cells?
-DNA damage activates p53, which either triggers DNA repair or initiates cell death (if the DNA cannot be repaired)
---p53 controls transcription of the gene encoding p21, a cell cycle inhibitor that allows DNA repair to occur
-mTOR regulates translation of p21 --> mTOR inhibition prevents p21-mediated cell cycle arrest
---Increases the likelihood that the DNA-damaged cell will progress through the cell cycle, and die (remember the discussion of alkylating agents and p53)
What are the pharmacokinetics of mTOR inhibitors?
-Oral admin; must be taken consistently (either with or without food) in order to minimize variability in drug concentration
-Metabolized by CYP 3A4 (drug interactions)
-Substrate for P-glycoprotein