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40 Cards in this Set

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Name the antimetabolites
Methotrexate
Pyrimidine analogues
Purine analogues
MOA of methotrexate
Folic acid analogue competitively inhibits DHFR (dihydro folate reductase)-> depletes folate necessary to perform single carbon transfers
Consequences of Methotrexate use
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
Pharmacology of MTX
Well absorbed from gut after ORAL admin
In high dose i.v. therapy 90% excreted in urine unchanged *renal clearance only mec of excretion
Does MTX bind plasma proteins?
Yes, tightly bound again b.c. renal clearance only mode of excretion monitor free plasma levels carefully.
Contributors to MTX effectiveness
MTX actively transported into cells.
What do MTX-polyglutamates do?
Metabolite of MTX, acts as folate antagonist
Two ways for MTX resistance
1. Reduced transport
2. Increase in DHFR activity (gene amplification)
* Nothing to do with delivery of the drug by decreased blood flow
Low dose toxicities of MTX
Myelosuppression and mucositis
High dose toxicities of MTX
(there are 5)
Fatal myelosuppression
Renal toxicity
Hepatotoxicity
Neurotoxicity
Teratogenicity
Leucovorin rescue
Leucovorin effectively aborts MTX toxicity by supplying reduced folate to cells in thus bypassing the inhibited reductase
Premetrexed
Just another folate antagonist
Pyrimidine Analogues 3 MOAs
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
5-Fluorouracil (5-FU) MOA (2- fold)
Pyrimidine analogue metabolized to 5-FdUMP a suicide inhibitor of thymidylate synthetase. *mentioned in review

5-FUTP gets incorporated into cellular RNA--> defective transcripts
PK of 5-FU: t1/2, metab
Short plasma t1/2
Metab to dihydrofluorouracil
What happens to 5-FU if it is given w/allopurinol or after MTX
Increased effectiveness
Toxicities of 5-FU
Myelosuppression
GI distress
Acute or chronic conjunctivitis
Name 2 other fluoropyrimidines
Floxuridine
Capecitabine (5-FU prodrug)
(ka-pe-SITE-a-been
What is Capecitabine metabolized by and used in?
Metabolized by thymidine phosphorylase- enzyme increased in certain tumors
Used in metastatic breast and colon cancer
Name two other uracil analogues and what they inhibit?
3-deazauridine- (-) CTP syn
6-azauridine- (-) orotodylate decarboxylase
Cytosine arabinoside (ARA C)structure and use
Analogue of cytidine in which ribose has been replaced by arabinose

Hematologic malignancies
MOA of cytosine arabinoside
ARA C (via deoxycytidine kinase) --> Ara CTP --> (-) DNA polymerase AND incorporates into DNA to cause defective ligation and premature chain termination
Metabolism and PK of Ara C
Ara C--> Ara U by cytidine deaminase
Ara CMP --> Ara UMP by dCMP deaminase
t1/2 = 7-20 mins

Take Home: Deamniase!
How do we increase the half life of Ara C?
Give with deaminase inhibitors.
Gemcitabine use aka...
(2'-2'difluorodexoycytidine)
(long word, must be effective against a lot of things)
Advanced breast cancer
Non small cell lung cancer
Pancreatic carcinoma
Ovarian cancer

OPAN
Toxities of Ara C (5)
Myelosuppression
Nausea
Vomiting
GI ulceration
Seizures
5-azacytidine
Metab, MOA, and use
5-azacytidine--> converted to 5-aza CTP

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

Use in Myelodysplastic syndromes
name 3 purine analogues
1. 6-mercaptopurine
2. 6-thioguanine
3. Pentostatin
MOA of the 6-thiopurines
Converted by hypoxanthine-guanine-phosphoribosyl transferase (HGPRT) to nucleoside monophosphates
What do the mononucleotides from the 6-thiopurines do?
1. Feedback (-) de novo purine syn

2. Competitively (-) biosynthetic rxns

3. Converted to triphosphates- incorporated into DNA and RNA
PK of 6-thiopurines: Two pathways of metabolism
Primary pathway~ S-methylation by thiopurine methyltransferase (TPMT)

Secondary pathway~ Oxidation by xanthine oxidase to 6-thiouric acid
Toxicities of 6-thiopurines
Myelosuppression
Hepatotoxicity
Pentostatin MOA
Purine analogue (-) adenosine deaminase, results in ↑ deoxyadenosine and dATP
Pentostatin Use and toxicity
Hairy cell leukemia

Neutropenia

Pen the Hairy Cell
Clofarabine
A deoxyadenosine analogue, when phosphorylated (-) DNA polymerase
This (-) ribonucleotide reductase, DNA synthesis and blocks cells at the G1/S boundary.
Hydroxyurea
Major side effect of Hydroxyurea
Leukopenia from bone marrow suppression
The prototypic enzyme for cancer chemotherapy. What does it do?
Asparaginase

converts Asparagine--> aspartate
MOA of Asparaginase
When intracellular asparagine is low it becomes an essential a.a.

Asparaginase decreases asparagine -->
(-) protein synthesis
Toxicities of Asparaginase
Decreased [] of secreted proteins
Hypersensitivity rxns