Differentiating Agents

Question 1

What are the differentiating agents?

Answer 1

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

Question 2

What is a hallmark of malignant transformation?

Answer 2

Differentiation block

Question 3

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

Answer 3

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

Question 4

What is a differentiation block

Answer 4

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

Question 5

What is an example of differentiation block?

Answer 5

• 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

Question 6

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

Answer 6

• Tretinoin, Arsenic Trioxide

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

Question 7

What is Tretinoin (ATRA)?

Answer 7

• 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)

Question 8

What toxicities are associated with Tretinoin (ATRA)?

Answer 8

• 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)

Question 9

What is arsenic trioxide (ATO)?

Answer 9

• 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

Question 10

What is Bexarotene?

Answer 10

• 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
• TERATOGENIC