Hopkins Pharmacology: Anti-Metabolites, Signal Transduction Inhibitors

folic acid mimic that inhibits dihydrofolate reductase (DHFR). this enzyme produces THF, which is the methyle and methylene donor for thymidine and purine synthesis. prodrug must be activated via enzymatic addition of several glutamates.

IV or oral formulations. very versatile cancer treatment (breast, colorectal, lymphoma, etc.). high dose MTX performed with reduced folates (leucovorin rescue).

mucositis, kidney damage, hepatotoxicity

reduced uptake from carriers, decrease in enzymes that add polyglutamate, DHFR gene amplification

inhibits ribonucleotide reductase, which reduces nucleotide triphosphates (NTPs) to dNTPs for DNA synth. complexes with active site non-heme iron.

leukemias, head and neck cancers

overexpression of reductase

"standard toxicities" (hair loss, neutropenia?)

active form (5-F-dUMP) covalently modifies thymidylate synthase, which converns dUMP to TMP. reduced TMP reduced thymidine pools for DNA synth. 5-FU activated by thymidine phosphorylase, thymidine kinase, and pyrimidine kinases. leucovorin cotreatment enhances 5-FU binding to TS.

IV and oral formulations. colorectal and breast cancer, usually in combination with other drugs.

bone marrow suppression

decreased activity of activating enzymes. dihydropyrimidine dehydrogenase inactivates 5-FU. inhibition with 5-ethynyluracil moves 5-FU towards activated drug pathway.

oral prodrug of 5-FU

works just like 5-FU

leucovorin pushes thymidylate enzyme towards inactive adduct formation via l'chatelier's principle by acting as the covalently bound coenzyme.

leucovorin is a highly bioavailable THF analog that rapidly replenishes THF to save rapidly dividing normal cells after cancer cells have been damaged beyond rescue.

activated to form mononucleotides that act as competitive inhibitors of enzymes for purine synthesis and get incorporated in DNA

prodrug for 6-mercaptopurine, which acts like 6-thioguanine

oral administration for leukemias

bone marrow suppression

inactivated by xanthine oxidase. decrease in HGPRTase (activating enzyme).

cytidine analog inhibitor of DNA polymerase

cytidine analog inhibitor of DNA polymerase

adenosine analog inhibitor of DNA polymerase

cytidine analog inhibitor of DNA polymerase

adenosine analog inhibitor of DNA polymerase

nucleoside analogs that are activated by deoxycytidylate kinase nucleoside diphosphate kinase. block DNA strand elongation.

pancreatic cancer

acute myelogenous leukemia

chronic lymphocytic leukemia

myelosuppression

decreased activity of activating enzymes, decreased nucleoside transport, cytarabine inactivated by cytidine deaminase

inhibitor of tyrosine kinases BCR-ABL, c-Kit TK, and PDGF-RK

treats hyperactive BCR-ABL in chronic myelogenous leukemia, c-KIT TK in gastrointestinal stromal tumors

amplification of oncogenic protein kinase, mutations in kinase catalytic domain

humanized monoclonal antibody that binds to extracellular region of HER2

treat 25% of breast cancers that exhibit HER2 overexpression

anti-EGFR monoclonal antibody used for colorectal and head and neck cancers.

EGFR tyrosine kinase inhibitor effective against non-small cell lunch cancer

boronic acid dipeptide inhibitor that targets chymotrypsin-like active site of the proteasome.

used against myeloma