Block 4: Chemo-Antimetabolites

Front 1

Name the antimetabolites

Back 1

Methotrexate
Pyrimidine analogues
Purine analogues

Front 2

MOA of methotrexate

Back 2

Folic acid analogue competitively inhibits DHFR (dihydro folate reductase)-> depletes folate necessary to perform single carbon transfers

Front 3

Consequences of Methotrexate use

Back 3

Inhibition of :
1. dUMP-> dTMP
2. Glycinamide ribonucleotide-> N-formyl glycinamide ribonucleotide
3. 5-aminoimidazole-4-carboxamide ribonucleotide-> 5-formaminoimidazole-4-carboxamide ribonucleotide

Step 1 Pyrimidine syn -(1st step)
Step 2 and 3: Syn of purine ring
Overall: Can't synthesize DNA

Front 4

Pharmacology of MTX

Back 4

Well absorbed from gut after ORAL admin
In high dose i.v. therapy 90% excreted in urine unchanged *renal clearance only mec of excretion

Front 5

Does MTX bind plasma proteins?

Back 5

Yes, tightly bound again b.c. renal clearance only mode of excretion monitor free plasma levels carefully.

Front 6

Contributors to MTX effectiveness

Back 6

MTX actively transported into cells.

Front 7

What do MTX-polyglutamates do?

Back 7

Metabolite of MTX, acts as folate antagonist

Front 8

Two ways for MTX resistance

Back 8

1. Reduced transport
2. Increase in DHFR activity (gene amplification)
* Nothing to do with delivery of the drug by decreased blood flow

Front 9

Low dose toxicities of MTX

Back 9

Myelosuppression and mucositis

Front 10

High dose toxicities of MTX
(there are 5)

Back 10

Fatal myelosuppression
Renal toxicity
Hepatotoxicity
Neurotoxicity
Teratogenicity

Front 11

Leucovorin rescue

Back 11

Leucovorin effectively aborts MTX toxicity by supplying reduced folate to cells in thus bypassing the inhibited reductase

Front 12

Premetrexed

Back 12

Just another folate antagonist

Front 13

Pyrimidine Analogues 3 MOAs

Back 13

Analogues of uridine or cytidine

1. Blocks syn. of nucleic acid
2. Metabolized to active inhibitor of nuclei acid syn
3. Incorporated into n.a. resulting in disrupted fxn

Front 14

5-Fluorouracil (5-FU) MOA (2- fold)

Back 14

Pyrimidine analogue metabolized to 5-FdUMP a suicide inhibitor of thymidylate synthetase. *mentioned in review

5-FUTP gets incorporated into cellular RNA--> defective transcripts

Front 15

PK of 5-FU: t1/2, metab

Back 15

Short plasma t1/2
Metab to dihydrofluorouracil

Front 16

What happens to 5-FU if it is given w/allopurinol or after MTX

Back 16

Increased effectiveness

Front 17

Toxicities of 5-FU

Back 17

Myelosuppression
GI distress
Acute or chronic conjunctivitis

Front 18

Name 2 other fluoropyrimidines

Back 18

Floxuridine
Capecitabine (5-FU prodrug)
(ka-pe-SITE-a-been

Front 19

What is Capecitabine metabolized by and used in?

Back 19

Metabolized by thymidine phosphorylase- enzyme increased in certain tumors
Used in metastatic breast and colon cancer

Front 20

Name two other uracil analogues and what they inhibit?

Back 20

3-deazauridine- (-) CTP syn
6-azauridine- (-) orotodylate decarboxylase

Front 21

Cytosine arabinoside (ARA C)structure and use

Back 21

Analogue of cytidine in which ribose has been replaced by arabinose

Hematologic malignancies

Front 22

MOA of cytosine arabinoside

Back 22

ARA C (via deoxycytidine kinase) --> Ara CTP --> (-) DNA polymerase AND incorporates into DNA to cause defective ligation and premature chain termination

Front 23

Metabolism and PK of Ara C

Back 23

Ara C--> Ara U by cytidine deaminase
Ara CMP --> Ara UMP by dCMP deaminase
t1/2 = 7-20 mins

Take Home: Deamniase!

Front 24

How do we increase the half life of Ara C?

Back 24

Give with deaminase inhibitors.

Front 25

Gemcitabine use aka...
(2'-2'difluorodexoycytidine)
(long word, must be effective against a lot of things)

Back 25

Advanced breast cancer
Non small cell lung cancer
Pancreatic carcinoma
Ovarian cancer

OPAN

Front 26

Toxities of Ara C (5)

Back 26

Myelosuppression
Nausea
Vomiting
GI ulceration
Seizures

Front 27

5-azacytidine
Metab, MOA, and use

Back 27

5-azacytidine--> converted to 5-aza CTP

5-aza CTP incorporated into RNA and (-) DNA methyltransferases

Use in Myelodysplastic syndromes

Front 28

name 3 purine analogues

Back 28

1. 6-mercaptopurine
2. 6-thioguanine
3. Pentostatin

Front 29

MOA of the 6-thiopurines

Back 29

Converted by hypoxanthine-guanine-phosphoribosyl transferase (HGPRT) to nucleoside monophosphates

Front 30

What do the mononucleotides from the 6-thiopurines do?

Back 30

1. Feedback (-) de novo purine syn

2. Competitively (-) biosynthetic rxns

3. Converted to triphosphates- incorporated into DNA and RNA

Front 31

PK of 6-thiopurines: Two pathways of metabolism

Back 31

Primary pathway~ S-methylation by thiopurine methyltransferase (TPMT)

Secondary pathway~ Oxidation by xanthine oxidase to 6-thiouric acid

Front 32

Toxicities of 6-thiopurines

Back 32

Myelosuppression
Hepatotoxicity

Front 33

Pentostatin MOA

Back 33

Purine analogue (-) adenosine deaminase, results in ↑ deoxyadenosine and dATP

Front 34

Pentostatin Use and toxicity

Back 34

Hairy cell leukemia

Neutropenia

Pen the Hairy Cell

Front 35

Clofarabine

Back 35

A deoxyadenosine analogue, when phosphorylated (-) DNA polymerase

Front 36

This (-) ribonucleotide reductase, DNA synthesis and blocks cells at the G1/S boundary.

Back 36

Hydroxyurea

Front 37

Major side effect of Hydroxyurea

Back 37

Leukopenia from bone marrow suppression

Front 38

The prototypic enzyme for cancer chemotherapy. What does it do?

Back 38

Asparaginase

converts Asparagine--> aspartate

Front 39

MOA of Asparaginase

Back 39

When intracellular asparagine is low it becomes an essential a.a.

Asparaginase decreases asparagine -->
(-) protein synthesis

Front 40

Toxicities of Asparaginase

Back 40

Decreased [] of secreted proteins
Hypersensitivity rxns