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Flashcards in Differentiating Agents Deck (10)
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What are the differentiating agents?

-Tretinoin [ATRA, RETIN-A]
-Arsenic Trioxide (ATO)


What is a hallmark of malignant transformation?

Differentiation block


What chemicals can induce tumor cell differentiation, ultimately leading to apoptosis?

-Vitamin D & its analogues
-Retinoids (Vitamin A derivatives like TRETINOIN)
-Rexinoids (multifunctional nuclear retinoid X receptor ligands such as BEXAROTENE)


What is a differentiation block

-Differentiation block is characteristic of several leukemias and results from the genetic defect


What is an example of differentiation block?

-t(15;17) translocation in acute promyelocytic leukemia (APL)
---This particular translocation creates a fusion protein (PML-RAR alpha) consisting of portions of retinoic acid receptor and promyelocytic leukemia protein


What two drugs in this class are approved for APL (acute promyelocytic leukemia)?

-Tretinoin, Arsenic Trioxide
-under investigation for use in other disease with a similar profile (as are many other drugs)


What is Tretinoin (ATRA)?

-In APL, activates the differentiation program (promyelocytes --> granulocytes) and promotes degradation of the PML-RAR fusion protein
-Doesn't kill cells; co-administered with either arsenic trioxide or anthracycline antibiotic to cause cell death
-Also used to treat acne (gel form)


What toxicities are associated with Tretinoin (ATRA)?

-Headache, dry skin, reversible hepatic enzyme abnormalities, bone tenderness, hyperlipidemia
-CNS toxicity: dizziness, anxiety, depression, confusion, agitation
-Differentiation syndrome (formerly called rationing acid syndrome): fever, dyspnea, weight gain, pulmonary infiltrates
---with or without pleural or pericardial effusions
---with or without leucocytosis
-Birth defects (teratogenic)


What is arsenic trioxide (ATO)?

-Heavy metal toxin that promotes cell death through apoptosis and necrosis
-Given in conjunction with TRETINOIN to cause death of differentiated granulocytes
-Also approved for relapsed APL (complete responses in 85% of patients)
-Generally well tolerated, but toxicities include:
---Arrhythmias (prolongation of QT interval)
---Leukocyte maturation syndrome similar to differentiation syndrome


What is Bexarotene?

-Rexinoid that selectively activates retinoid X receptors, which are involved in the regulation of cell growth and differentiation
-Approved for use with patients with cutaneous T-cell lymphoma that is refractory to skin-directed treatment
-Metabolized by CYP3A4 (potential for many drug interactions)
-Side effects include: GI symptoms, lipid abnormalities and pancreatitis