Antimetabolites, alkylators/plantinating agents

Describe how the anticancer mechanisms of action differ between the alkylators, platinating agents, and the antimetabolites.

• Alkylators: Covalently bind alkyl group to a biomolecule

• Platinating agents: Covalently bind to a biomolecule 

• Antimetabolites: 

  • Antifolates: DHFR inhibition → decreases folate (need for cell life)

  • Pyrimidine/purine analogs: Mimics bases → messes up DNA   

1. Describe where in the cell cycle of division the three classes of drugs

Describe where in the cell cycle of division the three classes of drugs discussed here have their activity, and how this affects their expected toxicity patterns.

• Alkylators & platinating agents: Prevent DNA replication and RNA transcription

• Antimetabolites: DNA synthesis

Class toxicities of Alkylating drugs

Notable toxicities most to least common:

• Myelosuppression

• Secondary cancer

• Hypersensitivity

• Hepatotoxic

• Pulm

• Neuro (seizures, neuropathy)

• Infx

• Cardiac

• GI

• Nephrotoxicity

Class toxicities of Antimetabolites

Notable toxicities most to least common: 

• Myelosuppression

• Hepatotoxicity

• Tumor lysis syndrome

• GI

• Hypersensitivity

• Neuro

• Infx

• Secondary cancer

How do the toxicities of cisplatin, carboplatin, and oxaliplatin differ?

• Cisplatin: High emesis and febrile neutropenia, ototoxicity, 

• Carboplatin: Mod emesis and some febrile neutropenia

• Oxaliplatin: Mod less emesis, peripheral neuropathy (acute and persistent)

Which of the following drugs requires a modification of dose for decreased renal function?

1. Ifosfamide (BBW)

2. Cisplatin (basically BBW)

3. Cyclophosphamide

4. Carboplatin

5. Oxaliplatin

6. Methotrexate

7. Fluorouracil

8. Capecitabine

9. Mercaptopurine

10. Gemcitabine

Which of the following drugs requires a modification of dose for decreased hepatic dysfunction?

Methotrexate

Fluorouracil

Capecitabine

Mercaptopurine

Gemcitabine

Why is leucovorin a required component of the treatment with high dose methotrexate?

“Rescue med” always used with high dose MTX because it reduces harmful effects against our healthy cells

What is the role of glucarpidase?

Promotes degradation and nonrenal elimination of MTX when there’s overexposure to MTX d/t renal dysfunction

What medications are recommended for the treatment of peripheral neuropathy associated with oxaliplatin?

Duloxetine

Hemorrhagic cystitis is a concern for what drugs, and what approaches are used to avoid it?

Aggressive IV hydration +/- diuresis

Start mesna if on ifosfamide (or high dose cyclophosphamide if hx of hematuria)

What drug interactions and polymorphisms affect the dosing of mercaptopurine, and how are these interactions or polymorphisms dealt with?

• Drug interaction:

  • Allopurinol inhibits xanthine oxidase (XO), which normally inactivates mercaptopurine.

  • This interaction increases mercaptopurine levels.

  • Management: Reduce mercaptopurine dose by 75% or avoid using both drugs together.

• Polymorphism:

  • TPMT (thiopurine methyltransferase) affects how mercaptopurine is inactivated.

  • Low TPMT activity = more active drug = risk of toxicity.

  • Management: Test TPMT activity and reduce dose if enzyme activity is low.