ALL Case Drugs

Question 1

Dexamethasone

Answer 1

Glucocorticoid receptor agonist (corticosteroid)- anti-inflammatory cytokines produced (IL 10) and pro-inflammatory inhibited (NFkB)

○Steroid so high volume of distribution as passes through membranes easy
○Binds to glucocorticoid receptors in cytoplasm (mimmics cortisol), causes receptor chaperone proteins to dissociate.
○Receptors can homodimerize, translocate to the nucleus, and transactivate gene expression (anti-inflammatory cytokines e.g. IL-1, IL-10).
○Can remain monomeric and repress the activity of transcription factors such as activating protein-1 (AP-1) or nuclear factor-κB (NF-κB) or tumour necrosis factor alpha (TNFa).
○Inhibits inflammatory cytokine production, also suppresses the migration of neutrophils and decreases lymphocyte colony proliferation.

Low doses = anti-inflammatory
High doses = immunosuppressive/cytotoxic effect (ALL induction)

●Effects:
○Can help kill cancer cells.
○Treat inflammation.
○Alleviate nausea and stimulate appetite.
○Immunosuppressant.

●Side Effects:
○Indigestion
○Insomnia
○Elevated Blood Glucose
○Delayed wound healing

Question 2

Asparaginase

Answer 2

●Effects:
○Enzyme that destroys Leukemic cells by breaking down asparagine

○Enzyme: Breaks down Asparagine (Amino Acid) into aspartic acid and ammonia this disrupts asparagine-dependent protein synthesis, stopping cell cycle and cell proliferation
○Some leukemic cells unable to synthesize asparagine due to a lack of asparagine synthase, dependent on an exogenous source of asparagine for survival.
○Depletion of asparagine kills the leukemic cells.
○Normal cells less affected by depletion due to their ability to synthesize asparagine.

●Side Effects:
○Allergic Reactions
○Hyperglycaemia
○Pancreatitis
○CNS Thrombosis

Question 3

Vincristine

Answer 3

vinca alkaloid (from a plant and like an alkali) that stops microtubules forming in mitosis

• Binds to beta tubulin
• Preventing polymerisation and therefore preventing formation of microtubules
• Causes mitosis to stop at metaphase- mitotic spindle cant form so chromosomes cant be pulled apart
• Cytotoxic

●Effects:
○Prevents division of cancer cells.
○Can target non-cancerous cells.

●Side Effects:
○Reduced Immune Response
○Hair Loss
○Sickness
○Fatigue

Question 4

Mercaptopurine

Answer 4

●Effects:
○Inhibition of DNA synthesis and cell replication.

MOA
○Structurally similar to purines (A and G).
○Produces many active metabolites within the body.
○Some metabolites (e.g. TIMP and MTIMP) inhibit enzymes essential to purine synthesis.
○Other metabolites (6-TG) act as fraudulent nucleotides, and are incorporated into DNA, resulting in strand termination, DNA damage, p53 activation and ultimately apoptosis.

Side effects:
Black, tarry stool
Cough
Dark urine
Nausea
Myelosuppression
Gastroenteritis
Liver Dysfunction

Question 5

Methotrexate

Answer 5

Binds to dihydrofolate reductase during S phase stopping DNA/RNA synthesis

MOA
○Binds to and inhibits dihydrofolate reductase during S phase
○This usually transforms an inactive form of folic acid into the active form, which is necessary for nucleotide synthesis.
○By inhibiting this enzyme, it inhibits purine nucleotide and thymidylate synthesis, and thus inhibits DNA and RNA synthesis.
○Results in DNA damage, activates p53 and thus apoptosis.
○Targets rapidly proliferating cells.

●Effects:
○Inhibits DNA/RNA synthesis.
○Prevents cell replication.
○Anti-inflammatory.
○Immunosuppressant.

●Side Effects:
○Hair Loss
○Immunosuppression
○Nausea
○Stomach Pain