04 Antimetabolites Wolf

Question 1

In general, what do Antimetabolites do?

Answer 1

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)

Question 2

What are the targets of Antimetabolites?

Answer 2

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

Question 3

What are the Fluoropyrimidine Antimetabolites?

Answer 3

5-Fluorouracil. 5-Fluorouridine

Question 4

What is the MOA of Antimetabolites?

Answer 4

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

Question 5

What is the MOA of 5-FU?

Answer 5

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

Question 6

What is F^18?

Answer 6

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

Question 7

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

Answer 7

All of its anabolites and catabolites

Question 8

What is F^19?

Answer 8

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

Question 9

What is Trapping?

Answer 9

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)

Question 10

What does F^19 MRS allow?

Answer 10

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

Question 11

What are the brand names of 5-FU?

Answer 11

Adrucil. Carac. Efudex. Fluoroplex. Fluorouracil

Question 12

How is 5-FU administered?

Answer 12

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

Question 13

How is 5-FU eliminated?

Answer 13

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

Question 14

What is a caution with 5-FU?

Answer 14

Cardiotoxicity

Question 15

What is Xeloda?

Answer 15

A new oral agent of 5-FU

Question 16

What is the metabolic activation of Xeloda?

Answer 16

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

Question 17

What are the Antifolates used?

Answer 17

Methotrexate. Trimetrexate

Question 18

How do Antifolates work?

Answer 18

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

Question 19

What are Thioguanine and 6-Mercaptopurine?

Answer 19

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

Question 20

What is the MOA of Thioguanine and 6-Mercaptopurine?

Answer 20

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

Question 21

When are Thioguanine and 6-Mercaptopurine usually used?

Answer 21

Used chiefly in the treatment of acute lymphoblastic leukemia

Question 22

How are Thioguanine and 6-Mercaptopurine administered?

Answer 22

Oral drugs

Question 23

What is Cytarabine used for?

Answer 23

Acute lymphocytic or myelogenous leukemia. Antimetabolite

Question 24

What is Fludarabine used for?

Answer 24

Chronic low-grade lymphocytic malignancies. Antimetabolite

Question 25

What is the MOA of Cytarabine?

Answer 25

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