Novel antifolate drugs

W. Thomas Purcell, David S Ettinger

Research output: Contribution to journalArticle

Abstract

Antimetabolites are active chemotherapeutic agents for many solid tumor and hematologic malignancies. Folate antagonists, purine analogues, and pyrimidine analogues are the three main categories of antimetabolites. Methotrexate, the most studied folate antagonist, is effective in many malignancies. Methotrexate inhibits dihydrofolate reductase, which leads to accumulation of polyglutamated folates, causing further inhibition of thymidylate synthase and glycinamide ribonucleotide formyltransferase. Subsequently, the lack of reduced folate substrates impairs synthesis of purine nucleotides, thymidylate, and certain amino acids, which can lead to cell death. However, methotrexate resistance develops through several mechanisms, including decreased folate carrier-mediated membrane transport, dihydrofolate reductase gene amplification, specific transcription-translational modifications, and downregulation of intracellular methotrexate polyglutamation. Antifolate drug development has focused on agents designed to overcome different aspects of methotrexate resistance. This article reviews the enzymatic targets for antifolates, describes the known mechanisms of antifolate resistance, and summarizes the current development of novel antifolate agents. Discussed specifically are trimetrexate, edatrexate, raltitrexed, pemetrexed, ZD9331, lometrexol, LY309887, GW?1843, OSI-7904(L), and nolatrexed, all of which have unique clinical pharmacology and are in various stages of development. The toxicity of antifolates has been sporadic and difficult to predict clinically. Supplementation with folic acid and vitamin B 12 has been shown to reduce the toxicity of pemetrexed without affecting efficacy and has increased the therapeutic index for this novel agent.

Original languageEnglish (US)
Pages (from-to)114-125
Number of pages12
JournalCurrent Oncology Reports
Volume5
Issue number2
StatePublished - Mar 2003
Externally publishedYes

Fingerprint

Folic Acid Antagonists
Folic Acid
Methotrexate
Pemetrexed
Pharmaceutical Preparations
Antimetabolites
Tetrahydrofolate Dehydrogenase
6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid
Trimetrexate
Hydroxymethyl and Formyl Transferases
Purine Nucleotides
Thymidylate Synthase
Clinical Pharmacology
Gene Amplification
Hematologic Neoplasms
Vitamin B 12
Neoplasms
Cell Death
Down-Regulation
Amino Acids

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Novel antifolate drugs. / Purcell, W. Thomas; Ettinger, David S.

In: Current Oncology Reports, Vol. 5, No. 2, 03.2003, p. 114-125.

Research output: Contribution to journalArticle

Purcell, WT & Ettinger, DS 2003, 'Novel antifolate drugs', Current Oncology Reports, vol. 5, no. 2, pp. 114-125.
Purcell, W. Thomas ; Ettinger, David S. / Novel antifolate drugs. In: Current Oncology Reports. 2003 ; Vol. 5, No. 2. pp. 114-125.
@article{9b980972d62b440480dc577453f204c6,
title = "Novel antifolate drugs",
abstract = "Antimetabolites are active chemotherapeutic agents for many solid tumor and hematologic malignancies. Folate antagonists, purine analogues, and pyrimidine analogues are the three main categories of antimetabolites. Methotrexate, the most studied folate antagonist, is effective in many malignancies. Methotrexate inhibits dihydrofolate reductase, which leads to accumulation of polyglutamated folates, causing further inhibition of thymidylate synthase and glycinamide ribonucleotide formyltransferase. Subsequently, the lack of reduced folate substrates impairs synthesis of purine nucleotides, thymidylate, and certain amino acids, which can lead to cell death. However, methotrexate resistance develops through several mechanisms, including decreased folate carrier-mediated membrane transport, dihydrofolate reductase gene amplification, specific transcription-translational modifications, and downregulation of intracellular methotrexate polyglutamation. Antifolate drug development has focused on agents designed to overcome different aspects of methotrexate resistance. This article reviews the enzymatic targets for antifolates, describes the known mechanisms of antifolate resistance, and summarizes the current development of novel antifolate agents. Discussed specifically are trimetrexate, edatrexate, raltitrexed, pemetrexed, ZD9331, lometrexol, LY309887, GW?1843, OSI-7904(L), and nolatrexed, all of which have unique clinical pharmacology and are in various stages of development. The toxicity of antifolates has been sporadic and difficult to predict clinically. Supplementation with folic acid and vitamin B 12 has been shown to reduce the toxicity of pemetrexed without affecting efficacy and has increased the therapeutic index for this novel agent.",
author = "Purcell, {W. Thomas} and Ettinger, {David S}",
year = "2003",
month = "3",
language = "English (US)",
volume = "5",
pages = "114--125",
journal = "Current Oncology Reports",
issn = "1523-3790",
publisher = "Current Science, Inc.",
number = "2",

}

TY - JOUR

T1 - Novel antifolate drugs

AU - Purcell, W. Thomas

AU - Ettinger, David S

PY - 2003/3

Y1 - 2003/3

N2 - Antimetabolites are active chemotherapeutic agents for many solid tumor and hematologic malignancies. Folate antagonists, purine analogues, and pyrimidine analogues are the three main categories of antimetabolites. Methotrexate, the most studied folate antagonist, is effective in many malignancies. Methotrexate inhibits dihydrofolate reductase, which leads to accumulation of polyglutamated folates, causing further inhibition of thymidylate synthase and glycinamide ribonucleotide formyltransferase. Subsequently, the lack of reduced folate substrates impairs synthesis of purine nucleotides, thymidylate, and certain amino acids, which can lead to cell death. However, methotrexate resistance develops through several mechanisms, including decreased folate carrier-mediated membrane transport, dihydrofolate reductase gene amplification, specific transcription-translational modifications, and downregulation of intracellular methotrexate polyglutamation. Antifolate drug development has focused on agents designed to overcome different aspects of methotrexate resistance. This article reviews the enzymatic targets for antifolates, describes the known mechanisms of antifolate resistance, and summarizes the current development of novel antifolate agents. Discussed specifically are trimetrexate, edatrexate, raltitrexed, pemetrexed, ZD9331, lometrexol, LY309887, GW?1843, OSI-7904(L), and nolatrexed, all of which have unique clinical pharmacology and are in various stages of development. The toxicity of antifolates has been sporadic and difficult to predict clinically. Supplementation with folic acid and vitamin B 12 has been shown to reduce the toxicity of pemetrexed without affecting efficacy and has increased the therapeutic index for this novel agent.

AB - Antimetabolites are active chemotherapeutic agents for many solid tumor and hematologic malignancies. Folate antagonists, purine analogues, and pyrimidine analogues are the three main categories of antimetabolites. Methotrexate, the most studied folate antagonist, is effective in many malignancies. Methotrexate inhibits dihydrofolate reductase, which leads to accumulation of polyglutamated folates, causing further inhibition of thymidylate synthase and glycinamide ribonucleotide formyltransferase. Subsequently, the lack of reduced folate substrates impairs synthesis of purine nucleotides, thymidylate, and certain amino acids, which can lead to cell death. However, methotrexate resistance develops through several mechanisms, including decreased folate carrier-mediated membrane transport, dihydrofolate reductase gene amplification, specific transcription-translational modifications, and downregulation of intracellular methotrexate polyglutamation. Antifolate drug development has focused on agents designed to overcome different aspects of methotrexate resistance. This article reviews the enzymatic targets for antifolates, describes the known mechanisms of antifolate resistance, and summarizes the current development of novel antifolate agents. Discussed specifically are trimetrexate, edatrexate, raltitrexed, pemetrexed, ZD9331, lometrexol, LY309887, GW?1843, OSI-7904(L), and nolatrexed, all of which have unique clinical pharmacology and are in various stages of development. The toxicity of antifolates has been sporadic and difficult to predict clinically. Supplementation with folic acid and vitamin B 12 has been shown to reduce the toxicity of pemetrexed without affecting efficacy and has increased the therapeutic index for this novel agent.

UR - http://www.scopus.com/inward/record.url?scp=0642316402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0642316402&partnerID=8YFLogxK

M3 - Article

C2 - 12583828

AN - SCOPUS:0642316402

VL - 5

SP - 114

EP - 125

JO - Current Oncology Reports

JF - Current Oncology Reports

SN - 1523-3790

IS - 2

ER -