(8) Antineoplastics: Antimetabolites (1.1-1.3) Flashcards
What is the precursor to dTMP?
dUMP
What cofactor does Thymidylate Synthase require?
THF
(tetrahydrofolate)
MOA: Methotrexate
Inhibits dihydrofolate reductase
Cell Cycle Specificity: Hydroxyurea
S phase
(Same for MTX and 5-FU)
Indications - Non-neoplastic (5) : Methotrexate
(1) Abortifacient
(2) Ectopic pregnancy
(3) Molar pregnancy
(4) Psoriasis
(5) Rheumatoid arthritis
* (And the neoplastic indications of trophoblastic tumors and choriocarcinomas)*
Adverse Effects (7) : Methotrexate
(1) Megaloblastic anemia
(2) Pulmonary fibrosis
(3) Hepatotoxicity
(4) Alopecia
(5) Mucositis
(6) Pancytopenia
(7) ⇒ Immunosuppression
What drug can be used to reverse the toxic effects of Methotrexate?
Folinic acid
(Trade name: Leucovorin ≠ Folate)
MOA: 5-Fluorouracil
Inhibits thymidylate synthase
(After activation by THF)
Name 2 adverse effects more common with 5-FU than MTX
(1) Severe diarrhea
(2) Cutaneous complications
Can you use Folinic Acid to treat 5-FU toxicity?
No
(It actually potentiates 5-FU)
What reaction does ribonucleotide reductase catalyze?
UDP ⇒ dUDP
(Notice progression from UDP → dUDP → dUMP)
MOA: Hydroxyurea
Ribonucleotide reductase inhibitor
(Also prevents HbS polymerization by ↑ [HbF])
What non-neoplastic indication does Hydroxyurea have?
Sickle cell anemia
(⇒ ↑ [HbF])
In purine synthesis, what is the precursor to IMP?
PRPP
(“Pentagon-shaped pedestal”)
What is a pro-drug of 6-mercaptopurine?
Azathioprine
What enzyme activates 6-mercaptopurine?
HGPRT
The synthesis of what purine intermediate is inhibited by 6-mercaptopurine?
IMP
Cell Cycle Specificity: Azathioprine
S phase
What is the primary neoplastic indication for AZA/6-MP?
Hematologic malignancies
Indications - Non-neoplastic (3) : AZA/6-MP
(1) Immunosuppressive
(2) Rheumatoid arthritis
(3) IBS
* (Note: AZA is NOT as effective as MTX in treating RA)*
Adverse Effects (4) : AZA/6-MP
(1) Myelosuppression
(2) ⇒ Immunosuppression
(3) Pancreatitis
(4) Hepatitis
What notable drug interaction does AZA/6-MP have?
Xanthine oxidase inhibitors
(I.e., Allopurinol, Febuxostat)
MOA: Mycophenolate mofetil
Inhibits IMP Dehydrogenase ⇒ ↓ GMP
What cell population is particularly vulnerable to Mycophenolate mofetil?
Lymphocytes
(Which require de novo synthesis of nucleotides. 6-MP/AZA likely has a similar profile)
Indications - Non-neoplastic (2) : Mycophenolate mofetil
(1) Immunosuppressive
(2) Rheumatoid arthritis
Adverse Effects (2) : Mycophenolate mofetil
(1) Severe GI distress
(2) Immunosuppression
Is Cladribine a purine or pyrimidine analog?
Purine
(Purines have 2 rings, purines = pu-‘rings’)
Cell Cycle Specificity: Cytarabine
S phase
MOA: Cladribine
Inhibits DNA polymerase
What is the most effective pharmacologic treatment for hairy cell leukemia?
Cladribine
Adverse Effects (2) : Cladribine/Gemcitabine
(1) Myelosuppression
(2) ⇒ Immunosuppression
Is Cytarabine a purine or pyrimidine analog?
Pyrimidine
What type of cancers is Cytarabine effective against?
Hematologic malignancies only
Is Gemcitabine a purine or pyrimidine analog?
Pyrimidine
What is the difference in the type of cancers Gemcitabine and Cytarabine treat?
(1) Gemcitabine: Hematologic AND solid tumors
(2) Cytarabine: Only hematologic
What type of cancers does Cytarabine treat?
Hematologic malignancies
