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40 Cards in this Set
- Front
- Back
Name the antimetabolites
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Methotrexate
Pyrimidine analogues Purine analogues |
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MOA of methotrexate
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Folic acid analogue competitively inhibits DHFR (dihydro folate reductase)-> depletes folate necessary to perform single carbon transfers
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Consequences of Methotrexate use
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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 |
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Pharmacology of MTX
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Well absorbed from gut after ORAL admin
In high dose i.v. therapy 90% excreted in urine unchanged *renal clearance only mec of excretion |
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Does MTX bind plasma proteins?
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Yes, tightly bound again b.c. renal clearance only mode of excretion monitor free plasma levels carefully.
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Contributors to MTX effectiveness
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MTX actively transported into cells.
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What do MTX-polyglutamates do?
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Metabolite of MTX, acts as folate antagonist
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Two ways for MTX resistance
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1. Reduced transport
2. Increase in DHFR activity (gene amplification) * Nothing to do with delivery of the drug by decreased blood flow |
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Low dose toxicities of MTX
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Myelosuppression and mucositis
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High dose toxicities of MTX
(there are 5) |
Fatal myelosuppression
Renal toxicity Hepatotoxicity Neurotoxicity Teratogenicity |
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Leucovorin rescue
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Leucovorin effectively aborts MTX toxicity by supplying reduced folate to cells in thus bypassing the inhibited reductase
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Premetrexed
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Just another folate antagonist
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Pyrimidine Analogues 3 MOAs
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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 |
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5-Fluorouracil (5-FU) MOA (2- fold)
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Pyrimidine analogue metabolized to 5-FdUMP a suicide inhibitor of thymidylate synthetase. *mentioned in review
5-FUTP gets incorporated into cellular RNA--> defective transcripts |
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PK of 5-FU: t1/2, metab
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Short plasma t1/2
Metab to dihydrofluorouracil |
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What happens to 5-FU if it is given w/allopurinol or after MTX
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Increased effectiveness
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Toxicities of 5-FU
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Myelosuppression
GI distress Acute or chronic conjunctivitis |
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Name 2 other fluoropyrimidines
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Floxuridine
Capecitabine (5-FU prodrug) (ka-pe-SITE-a-been |
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What is Capecitabine metabolized by and used in?
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Metabolized by thymidine phosphorylase- enzyme increased in certain tumors
Used in metastatic breast and colon cancer |
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Name two other uracil analogues and what they inhibit?
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3-deazauridine- (-) CTP syn
6-azauridine- (-) orotodylate decarboxylase |
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Cytosine arabinoside (ARA C)structure and use
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Analogue of cytidine in which ribose has been replaced by arabinose
Hematologic malignancies |
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MOA of cytosine arabinoside
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ARA C (via deoxycytidine kinase) --> Ara CTP --> (-) DNA polymerase AND incorporates into DNA to cause defective ligation and premature chain termination
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Metabolism and PK of Ara C
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Ara C--> Ara U by cytidine deaminase
Ara CMP --> Ara UMP by dCMP deaminase t1/2 = 7-20 mins Take Home: Deamniase! |
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How do we increase the half life of Ara C?
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Give with deaminase inhibitors.
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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 |
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Toxities of Ara C (5)
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Myelosuppression
Nausea Vomiting GI ulceration Seizures |
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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 |
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name 3 purine analogues
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1. 6-mercaptopurine
2. 6-thioguanine 3. Pentostatin |
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MOA of the 6-thiopurines
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Converted by hypoxanthine-guanine-phosphoribosyl transferase (HGPRT) to nucleoside monophosphates
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What do the mononucleotides from the 6-thiopurines do?
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1. Feedback (-) de novo purine syn
2. Competitively (-) biosynthetic rxns 3. Converted to triphosphates- incorporated into DNA and RNA |
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PK of 6-thiopurines: Two pathways of metabolism
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Primary pathway~ S-methylation by thiopurine methyltransferase (TPMT)
Secondary pathway~ Oxidation by xanthine oxidase to 6-thiouric acid |
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Toxicities of 6-thiopurines
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Myelosuppression
Hepatotoxicity |
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Pentostatin MOA
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Purine analogue (-) adenosine deaminase, results in ↑ deoxyadenosine and dATP
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Pentostatin Use and toxicity
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Hairy cell leukemia
Neutropenia Pen the Hairy Cell |
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Clofarabine
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A deoxyadenosine analogue, when phosphorylated (-) DNA polymerase
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This (-) ribonucleotide reductase, DNA synthesis and blocks cells at the G1/S boundary.
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Hydroxyurea
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Major side effect of Hydroxyurea
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Leukopenia from bone marrow suppression
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The prototypic enzyme for cancer chemotherapy. What does it do?
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Asparaginase
converts Asparagine--> aspartate |
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MOA of Asparaginase
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When intracellular asparagine is low it becomes an essential a.a.
Asparaginase decreases asparagine --> (-) protein synthesis |
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Toxicities of Asparaginase
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Decreased [] of secreted proteins
Hypersensitivity rxns |