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In general, what do Antimetabolites do?

They are agents that act on and interfere with cell processes in the tumor cell by mimicking a naturally occurring biochemical. They may act on processes that affect the viability of existing tumor cells: energy and translation (targets: cell enzymes and RNA). Or they may act on processes that affect the viability of future tumor cells: replication (target: DNA)


What are the targets of Antimetabolites?

Cellular targets (DNA and RNA). Vehicles that are used to attach DNA and RNA. Natural purines and pyrimidines


What are the Fluoropyrimidine Antimetabolites?

5-Fluorouracil. 5-Fluorouridine


What is the MOA of Antimetabolites?

Agents that act on and interfere with cell processes in the tumor cell by MIMICKING a naturally occurring biochemical and taking its place - up to a point


What is the MOA of 5-FU?

An analog of uracil and is first metabolized by the same enzymes that act on uracil: transport into the tumor cell, incorporation into RNA and DNA, and binding to the thymidilate synthase. Once these first sets of biochemical steps have occurred, further processing of this altered uracil is impaired. The antimetabolic effect has now taken place


What is F^18?

Positron emitter. Reasonably long-lived (108 min), allowing for a 12-20 hour window. Single, very stable carbon-fluorine bond. Significant number of fluorinated drugs in clinical use. Studies could be combined with F^19 NMR


What compounds do we see when we image after the administration of F^18-5-FU?

All of its anabolites and catabolites


What is F^19?

High NMR Sensitivity. 100% natural abundance. Wide chemical shift range (200ppm). No natural fluorinated compounds in the human body (except some F-). Studies could be combined with F^18 PET


What is Trapping?

Trapping of products in cells can occur by one of two mechanisms. 1) When metabolism occurs to agents that can either no longer leave the cell or be metabolized further (metabolic trapping). 2) When the product is transported into cells, but its transport out of the cell is slow or nil (membrane-driven trapping)


What does F^19 MRS allow?

The measurement of the intratumoral pharmacokinetics of fluorinated drugs (e.g. 5-FU, capecitabine, UFT, gemcitabine, etc) following their administration to patients


What are the brand names of 5-FU?

Adrucil. Carac. Efudex. Fluoroplex. Fluorouracil


How is 5-FU administered?

Topically or parenterally. Given as a bolus or as infusions lasting from 1 day to 28 days. Intra-arterial administration, intra-peritoneal administration


How is 5-FU eliminated?

85% is extracted by the liver in each passage where it is catabolized by DPD (which follows a circadian rhythm)


What is a caution with 5-FU?



What is Xeloda?

A new oral agent of 5-FU


What is the metabolic activation of Xeloda?

1) The ether function allows intestinal transit with no uptake in the intestinal wall. 2) The amino group makes this a cytidine and allows transfer using the cytidine transporter. The absence of the hydroxyl function of 5' does not allow incorporation into RNA and allows this intermediate to be hydrolyzed to the free base


What are the Antifolates used?

Methotrexate. Trimetrexate


How do Antifolates work?

1) Competes with folates for transport into cells (MTX) (TMTX is passive diffusion). Deplete the intracellular THF pools (both). Saturate DHF binding sites (both)


What are Thioguanine and 6-Mercaptopurine?

They act as antimetabolites and are active in the S-phase of cell division


What is the MOA of Thioguanine and 6-Mercaptopurine?

They can undergo triphosphorylation and be incorporated into DNA in place of guanine, leading to a derangement in the DNA message. Secondly, they can be metabolized to a nucleotide that inhibits hypoxanthine-guanine phosphoribosyltransferase, an enzyme essential to purine biosynthesis, which is needed for RNA and DNA synthesis. Together, these effects lead to cell death


When are Thioguanine and 6-Mercaptopurine usually used?

Used chiefly in the treatment of acute lymphoblastic leukemia


How are Thioguanine and 6-Mercaptopurine administered?

Oral drugs


What is Cytarabine used for?

Acute lymphocytic or myelogenous leukemia. Antimetabolite


What is Fludarabine used for?

Chronic low-grade lymphocytic malignancies. Antimetabolite


What is the MOA of Cytarabine?

Intracellularly, Cytarabine is metabolized be deoxycytidine kinases to form 1-beta-D-arabinofuranosylcytosine-5'-triphosphate (Ara-CTP). Ara-CTP competitively inhibits DNA polymerase-alpha and halts DNA elongation and repair