Lecture 7: Pharmacology of Cancer & Malignancies

Question 1

Group 1 of chemo drugs

Answer 1

Antimetabolites

Question 2

What is the mechanism of action of the antimetabolites?

Answer 2

Inhibit protein synthesis

Question 3

What chemo drug agents make the antimetabolite group

Answer 3

• Methotrexate: folic acid antagonist (inhibit reduction of dihydrofolate into tetrahydrofolate so active folate is not produced and DNA synthesis remains inhibited)
• 6 mercaptopurine: Inhibits biosynthesis of purine ring, thus inhibiting DNA synthesis
• Pyrimidine analogues:
  -5 Fluororacil (5-FU): Inhibits thymidylate synthetase
  -Gemcitabine: Inhibit DNA synthesis and polymerase
  -&Cytarabine: Inhibit DNA synthesis and polymerase

Question 4

Which of the antimetabolites, in group 1 of the Chem drugs need activation to triphosphate before they can incorporate to DNA and bind into DNA polymerase?

Answer 4

• 6 mercaptopurine
• Pyrimidine analogues

Question 4

Name the 2 target enzymes of methotrexate

Answer 4

• Dihydrofolate reductase
• Thymidylate synthetase

Question 4

Why you should never give methotrexate together with 5 FU?

Answer 4

Methotrexate inhibits folate production, whereas 5-FU needs folate to inhibit thymidylate synthetase

• So just combining them will lead to unnecessary toxicity since 5-FU will have no anti-cancer effects coz it will not be able to inhibit thymidylate synthetase in the absence of folate

Question 5

What are the clinical uses of methotrexate?

Answer 5

• Acute lymphoblastic
  leukaemia
• Burkits lymphoma
• Choriocarcinoma
• Head and neck tumours
• Breast / bone / bladder
• Rheumatoid arthritis
• CI: Liver / renal
  impairment or dose
  reduction

Question 6

List the methotrexate kinetics

Answer 6

• Administered Ora l/ IV / intrathecal
• Accumulate Kidney, liver ,
  epithelium
• Requires addition of
  glutamic acid residues for
  cell entrapment

Question 7

Clinical uses of premetrexed

Answer 7

• Pleural mesothelioma
  (with cisplatin)
• Metastatic NSC lung cancer

Question 8

Name the adverse drug reactions following the use of methotrexate and Premetrexed

Answer 8

 Myelosuppression
 N/V/D
 Hepatotoxicity (LD & HD)
 Renal failure
 Pneumonitis
 Mucositis
 Stomatitis
 Drug interactions:
 NSAIDS, omeprazole,
warfarin, penicillin, cephs

Question 9

Patients given methotrexate are to be given Folinic acid rescue
therapy as well. What does receiving folinic acid rescue therapy entail?

Answer 9

 In folinic acid rescue therapy, patients receive Leucovorin (after 24 hrs of receiving methotrexate)
 Leucovorin is a formyl form of tetrahydrolate acid (N5 - formyl THF)
 Leucovorin Counteract MTX toxicity
 Augment cytotoxic activity of 5-Fluorouracil
 Calcium levofolinate =
leucovorin