Pathway Antimetabolite Pathway - Folate Cycle, Pharmacodynamics

Pharmacodynamics
Model non-tissue specific cancer cell displaying candidate genes which may be involved in the pharmacodynamics of antimetabolite drugs acting on the folate cycle.
Antimetabolite Pathway - Folate Cycle, Pharmacodynamics
raltitrexed fluoropyrimidines perretrexed leucovorin mtx Thiopurines tyms dhfr cbs mthfr shmt1 ppat gart atic mtr mthfd1 mtrr mthfd1 mthfs mthfd1 ada
clickable pathway icons

Description

Antimetabolite drugs were the first widely successful class of drugs developed by rational design for the treatment of cancer [Articles:18860765, 14803432]. They include analogues of purines (thiopurines such as 6-mercaptopurine, 6-thioguanine and azathioprine) pyrimidines (fluoropyrimidines such as 5-fluorouracil, tegafur and capecitabine) and antifolates (methotrexate, pemetrexed and raltitrexed). Although some were designed in the 1950's these drugs are still used today in treatment of leukemia, breast cancer, colorectal cancer and many other cancers [Article:2679902]. Some of these drugs, for example methotrexate and azathioprine, are also used in the management of inflammatory conditions such as rheumatoid arthritis.

The purpose of this pathway is to show how the pharmacodynamics (PD) for many of the antimetabolite drugs are interconnected. The figure links various antimetabolite drugs and shows how their actions overlap. In order to increase efficacy, antimetabolite drugs are commonly used in combination with other antineoplastic drugs including sometimes other antimetabolites (eg. Methotrexate and 6-mercaptopurine for treatment of ALL) although care much be taken to avoid overlapping side effect profiles [Article:11008002]. Normal intermediates, such as Leucovorin, can also be used to enhance antimetabolite drug action [Article:1911453]. All the antimetabolite drugs depicted here interact in some way with the folate cycle also known as folate-mediated one-carbon metabolism [Articles:16207145, 19952870]. Folate-mediated one-carbon metabolism is essential for synthesis of DNA and activated methyl groups that are required for DNA methylation, regulation of chromatin structure, remethylation of homocysteine as well as methylation of proteins and drugs [Article:19812215]. Disturbance of the folate cycle, whether by inadequate vitamin intake, or variants effecting expression or activity of the genes and products involved, has been associated with a variety of disease conditions including neural tube defects in developing embryos, vascular diseases, cognitive disorders and cancers, reviewed in [Article:11683553]. It is because the folate cycle is so critical for DNA synthesis and cellular functions, that it is a good target for antineoplastic drugs, however it may also be responsible for the drugs adverse effects.

Folate is absorbed from the diet, from green leafy vegetables and as folic acid from supplements or enriched foods. Metabolism of folate to different forms can take place in different cell compartments including the cytoplasm (as shown above), mitochondrion and nucleus (not depicted). Metabolism occurs as part of large multienzyme complexes that perform specific parts of the cycle, reviewed in [Article:19812215].

Pharmacogenomics
There are well known variants for many of the genes involved in the folate pathway including: TYMS:TSER (rs34743033), TYMS:1494del TTAAAG (rs34489327), TYMS:TSER*3G>C (no rs#), DHFR:19bpdel (rs70991108), MTHFR:677C>T (rs1801133), MTHFR:1298A>C (rs1801131), MTR:Asp919Gly (rs1805087), MTRR:66A>G (rs1801394), CBS:844ins68 (no rs#) [Article:19581920].

However, there are currently no guidelines for pharmacogenomic testing involving any of the genes depicted in this pathway (TPMT testing is suggested for thiopurines but this gene is not directly involved in the folate pathway). Several of these variants in the folate pathway are also associated with disease conditions such as neural tube defects and cardiovascular disorder. For more details on these variants and their PGx implications see the VIP and variant annotations and the individual drug pathways:

* Very Important Pharmacogene Methylenetetrahydrofolate reductase (MTHFR)
* Very Important Pharmacogene Thymidylate synthase (TYMS)
* Annotated variants for Dihydrofolate reductase (DHFR)
* Annotated variants for Methionine synthase (MTR)
* Annotated variants for Methionine synthase reductase (MTRR)
* Annotated variants for Methylenetetrahydrofolate dehydrogenase (MTHFD1)
* Annotated variants for Cystathionine beta synthase (CBS)
* Fluoropyrimidine Pathway (PD, PK)
* Methotrexate Pathway
* Thiopurine Pathway

Authors: Caroline F. Thorn.
Citation:
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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History:
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (13)

Drugs/Drug Classes (6)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
10-formyltetrahydrofolate IMP
5,10-methylenetrahydrofolate 5,10-methyltetrahydrofolate MTHFD1 14647408, 19812215
5,10-methylenetrahydrofolate 5-methyl tetrahyrofolate MTHFR 14647408, 15797993, 19812215
5,10-methylenetrahydrofolate dihydrofolate TYMS 11986237, 12084458, 12604405, 19812215, 19902562
5,10-methyltetrahydrofolate 10-formyltetrahydrofolate MTHFD1 14647408, 19812215
5,10-methyltetrahydrofolate 5-formyltetrahydrofolate MTHFS 19812215, 3801490
5-methyl tetrahyrofolate tetrahydrofolate cyanocobalamin, MTR, MTRR 19812215
ADA ADA ATIC, GART
adenosine inosine ADA 12106498
ADP ATP
AMP adenosine
AMP ADP
ATIC ATIC methotrexate
DHFR DHFR methotrexate, pemetrexed 12084458, 14662327, 16637794
dihydrofolate tetrahydrofolate DHFR 12084458, 14529544, 19812215
dUMP dTMP TYMS
GART GART methotrexate, pemetrexed 16637794
glycine serine SHMT1 19812215
homocysteine cystathionine CBS 16013960, 19812215
homocysteine methionine cyanocobalamin, MTR, MTRR 15797993, 17611986, 19812215
IMP AMP
IMP IMP Black Box: de novo purine synthesis
IMP inosine
inosine hypoxanthine
methionine S-adenosylmethionine 19812215
MTHFR MTHFR S-adenosylmethionine
PPAT PPAT methotrexate, purine analogues 10432311, 5788533, 9744080
protein methylated protein
S-adenosylhomocysteine homocysteine
S-adenosylmethionine S-adenosylhomocysteine 19812215
tetrahydrofolate 10-formyltetrahydrofolate MTHFD1
tetrahydrofolate 5,10-methylenetrahydrofolate SHMT1 15797993, 19812215
TYMS TYMS leucovorin, methotrexate, pemetrexed, Pyrimidine analogues, raltitrexed 12084458, 12724731, 12819937, 15638735, 16637794

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