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Flashcards in mTOR Inhibitors Deck (7)
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1

What are the two mTOR inhibitors?

-Everolimus
-Temsirolimus

2

What are there 3 MOA?

1. Reducing cell growth and proliferation
2. Prevention of angiogenesis
3. Synergy with drugs that damage DNA

3

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

4

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

5

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)

6

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

7

What are the side effects of mTOR inhibitors?

-Hypersensitivity
-Increased risk of lymphomas (like other immunosuppressants), particularly of the skin and infection
-Angioedema
-Kidney arterial and venous thrombosis
-Delays in wound healing
-Hyperlipidemia
-Nephrotoxicity and proteinuria
-Male infertility