Chemo Lecture 2: Folate and Purine antimetabolites - Fitzpatrick

Question 1

Which antimetabolites drugs are anti-folate

Answer 1

Methotrexate and Pemetrexed

Question 2

What is the MOA of methotrexate (MTX)?

Answer 2

MTX inhibitors DHFR –> blocks synthesis of thymidine, methionine and serine. AND Metabolite MTX (glu)n inhibits GAR and AICAR transformylase which blocks synthesis of purines

Question 3

Pemetrexed is a potent inhibitor of 1 and 2. It’s 1000x less potent inhibition of DHFR compared to MTX, but it’s useful because it can circumvent resistance of 3

Answer 3

1. Thymidylate synthease
2. GAR transformylase
3. MTX

Question 4

Therapeutic use of Methotrexate

Answer 4

• Pediatric Leukemias (Acute lymphoblastic anemia)
• Primary CNS lymphoma
• NHL
• Choriocarcinoma (monotherapy)

Question 5

Therapeutic uses of pemetrexed

Answer 5

• Malignant pleural mesohelioma in combo with cisplatin

- refractory NSCLC

Question 6

Therapeutic use of methotrexate is dose dependent. Differentiate what dose, intermediate dose and low dose MTX are used for

Answer 6

1. High Dose: CNS prophylaxis in pts w/ Leukemia and high risk lymphoma - followed by rescue with leucovorin (depends on rapid clearance of MTX by kidneys)
2. Intermediate dose: malignant gestational trophoblastic disease (e.g. Choriocarcinoma)
3. Low dose: Intrathecal for CNS prophylaxis; i.v. for bladder, desmoid tumors; oral for ALL, APL

Question 7

Dose-limiting tox of Methotraxate

Answer 7

• Pregnancy category D
• Bone marrow suppression (use leucovorin) ;
• GI TOX (diarrhea, small bowel ulcers and bleeding and perforation)
• mucositis
• High dose –> renal cystalluria of MTX and renal failure (high dose requires leucovorin rescue and thus if can’t be cleared leucovorin can’t be used)
• Other Tox: neurotoxicity; pulmonary infiltrates; hepatotoxicity

Question 8

Dose limiting tox of Pemetrexed

Answer 8

• Pregnancy category D
• Bone marrow suppression
• caution in pts w/ even mild to moderate renal insufficiency (e..g co-tx with NSAIDS)

Question 9

Intermediate/low dose MTX 80-90% of MTX is cleared by

Answer 9

renal excretion

Question 10

High dose MTX can lead to cystalluria tubular obstruction via which metabolite?

Answer 10

High dose MTX has hepatic metabolism which forms 7-hydroxy-MTX and is the inactive and less soluble form which can cause tubular obstruction and damage

Question 11

MOA of pemetrexed

Answer 11

competitive inhibition of TS and gAR transformylase.

- neglifible effect of DHFR compared to MTX

Question 12

What antineoplastic drugs are are purine-antimetabolites?

Answer 12

• 6 - Merceptopurine (6-MP)
• 6-Thioguanine (6-TG)
• Fludarabine
• Cladirbine

Question 13

What is the MOA of 6-MP and 6-TG

Answer 13

inhibits purine ring biosynthesis and nucleotide interconversion –> disrupts DNA and RNA integrity

Question 14

What is the MOA of Fludrabine (2-F-araA)

Answer 14

Tumor cell kinases convert 2-F-araA to nucleotide triphosphates –> inserted into DNA, RNA and disrupt DNA and RNA synthesis

Question 15

What is the MOA of Cladribine (2-Cl-deoxyadenosine)

Answer 15

• Tumor cell kinases convert it to nucleotide analogs; inhibits DNA synthesis; also potent inhibitor of ribonucleotide reductase

Question 16

Therapeutic use of 6-MP

Answer 16

Maintenance of remission in ALL

Question 17

Therapeutic use of 6-TG

Answer 17

Acute non-lymphocytic leukemia (used w/ daunoribicin and cytarabine)

Question 18

Therapeutic use of Fludarabine

Answer 18

Mainly used for CLL

Question 19

Therapeutic use of Cladribine

Answer 19

Mainly Hairy cell leukemia

Question 20

Dose limiting tox of 6MP and 6TG

Answer 20

• myelosuppression

- hepatotoxicity

Question 21

Dose limiting tox of Fludarabine

Answer 21

Myelosuppression; opportunisitc infection

Question 22

Dose limiting tox of cladribine

Answer 22

Myelosuppression; drug fever

Question 23

Hepatic inactivation of 6MP is done by what enzyme to produce what inactive metabolite?

Answer 23

1. Xanthine oxidase (XO), produces 6-thiouric acid

2. Thiopurine methyltransferase (TPMT) –> methyl-6-MP

Question 24

Bioactivation of 6MP is done by what enzyme to produce what active metabolite?

Answer 24

Hypoxanthine phosphoribosyltransferase (HPRT) –> 6-thio-inosine monophosphate (TIMP). TIMP then gets further metabolized to produce the active antineoplastic products: 6-methyl- TIMP ribonucleotides by TPMT and this is the main MOA for this drug; and TXMP 6-thioxanthine monophosphate by inosine monophosphate dehydrogenase (IMPDH)

Question 25

6MP is often coadministered which what other drug?

Answer 25

allopurinol (XO inhibitor) which increases the availability of 6MP and thus dose of 6MP must be adjusted

Question 26

what enzyme activates/inactivates 6TG?

Answer 26

activated by hypoxanthine ribosyltransferase (HPRT)

inactivated by Thiopurine methyltransferase (TPMT)

Question 27

Fludarabine and Cladribine are chemical analogs of which purine?

Answer 27

Adenosine

Question 28

MOA of Fludarabine and cladribine

Answer 28

enters tumor cells by active transport and various kinaes enzymes in the tumor converts them to necleotide mono, di, triphosphates and deoxynuceoltides di, triphosphates. These active metabolites inhibit DNA pol and can incorporate into DNA and RNA .

• Cladribine deoxynucleotide metabolites can also inhibi ribonucleotide reductase and deplete cellular pools of dNTP needed for DNA synthesis

Question 29

Pyrimidine antimetabolites, folate anitmetabolites and purine antimetabolites are all active during which phase of the cell cycle?

Answer 29

S phase