New concepts for the development and use of antifolates

Edward Chu, Jean L. Grem, Patrick G. Johnston, Carmen J. Allegra

Research output: Contribution to journalReview article

22 Citations (Scopus)

Abstract

Approximately one-third of all cases of colorectal carcinoma present in an advanced and, therefore, incurable stage. For these patients, the development of new chemotherapeutic strategies is of central importance. Biochemical modulation of 5-fluorouracil (5-FU) has resulted in approximately a two-fold increase in activity of 5-FU. Recent preclinical investigations suggest that interferon can also modulate the activity of 5-FU and may result in enhanced response rates in patients. One of the critical mechanisms of resistance to 5-FU appears to be the acute induction in thymidylate synthase (TS) levels following therapy with inhibitors of this enzyme. This mechanism is based on a novel autoregulatory feedback pathway wherein the TS protein regulates its own translational efficiency. Regulatory function of the enzyme is dependent on its state of occupancy by either the physiologic ligands or inhibitors, including flouropyrimidines and antifolates. Ongoing efforts are directed towards utilizing knowledge of this protein/messenger RNA interaction for therapeutic benefit. Given the importance of TS, our laboratory has developed antibodies capable of quantitating the levels of this enzyme in fresh or paraffin-embedded tissues. Preliminary investigations suggest that the level of TS has prognostic importance in patients with rectal carcinoma and may be used to predict responsiveness to fluoropyrimidine agents. Novel strategies utilizing dual modulation of 5-FU with leucovurin and interferon are under investigation in both the advanced and adjuvant disease settings. Emerging mechanistic concepts regarding TS, along with the development of new, more potent inhibitors will hopefully result in future therapeutic gains.

Original languageEnglish (US)
Pages (from-to)41-46
Number of pages6
JournalSTEM CELLS
Volume14
Issue number1
DOIs
StatePublished - Jan 1 1996

Fingerprint

Folic Acid Antagonists
Thymidylate Synthase
Fluorouracil
Interferons
Enzyme Inhibitors
Enzymes
Paraffin
Colorectal Neoplasms
Proteins
Therapeutics
Ligands
Carcinoma
Messenger RNA
Antibodies

Keywords

  • Antifolates
  • Biochemical modulation
  • Enzyme regulation
  • Interferon
  • Monoclonal antibodies
  • Thymidylate synthase
  • immunohistochemistry

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

New concepts for the development and use of antifolates. / Chu, Edward; Grem, Jean L.; Johnston, Patrick G.; Allegra, Carmen J.

In: STEM CELLS, Vol. 14, No. 1, 01.01.1996, p. 41-46.

Research output: Contribution to journalReview article

Chu, E, Grem, JL, Johnston, PG & Allegra, CJ 1996, 'New concepts for the development and use of antifolates', STEM CELLS, vol. 14, no. 1, pp. 41-46. https://doi.org/10.1002/stem.140041
Chu, Edward ; Grem, Jean L. ; Johnston, Patrick G. ; Allegra, Carmen J. / New concepts for the development and use of antifolates. In: STEM CELLS. 1996 ; Vol. 14, No. 1. pp. 41-46.
@article{30ea3182d6bc4b699373b378c1be5381,
title = "New concepts for the development and use of antifolates",
abstract = "Approximately one-third of all cases of colorectal carcinoma present in an advanced and, therefore, incurable stage. For these patients, the development of new chemotherapeutic strategies is of central importance. Biochemical modulation of 5-fluorouracil (5-FU) has resulted in approximately a two-fold increase in activity of 5-FU. Recent preclinical investigations suggest that interferon can also modulate the activity of 5-FU and may result in enhanced response rates in patients. One of the critical mechanisms of resistance to 5-FU appears to be the acute induction in thymidylate synthase (TS) levels following therapy with inhibitors of this enzyme. This mechanism is based on a novel autoregulatory feedback pathway wherein the TS protein regulates its own translational efficiency. Regulatory function of the enzyme is dependent on its state of occupancy by either the physiologic ligands or inhibitors, including flouropyrimidines and antifolates. Ongoing efforts are directed towards utilizing knowledge of this protein/messenger RNA interaction for therapeutic benefit. Given the importance of TS, our laboratory has developed antibodies capable of quantitating the levels of this enzyme in fresh or paraffin-embedded tissues. Preliminary investigations suggest that the level of TS has prognostic importance in patients with rectal carcinoma and may be used to predict responsiveness to fluoropyrimidine agents. Novel strategies utilizing dual modulation of 5-FU with leucovurin and interferon are under investigation in both the advanced and adjuvant disease settings. Emerging mechanistic concepts regarding TS, along with the development of new, more potent inhibitors will hopefully result in future therapeutic gains.",
keywords = "Antifolates, Biochemical modulation, Enzyme regulation, Interferon, Monoclonal antibodies, Thymidylate synthase, immunohistochemistry",
author = "Edward Chu and Grem, {Jean L.} and Johnston, {Patrick G.} and Allegra, {Carmen J.}",
year = "1996",
month = "1",
day = "1",
doi = "10.1002/stem.140041",
language = "English (US)",
volume = "14",
pages = "41--46",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "1",

}

TY - JOUR

T1 - New concepts for the development and use of antifolates

AU - Chu, Edward

AU - Grem, Jean L.

AU - Johnston, Patrick G.

AU - Allegra, Carmen J.

PY - 1996/1/1

Y1 - 1996/1/1

N2 - Approximately one-third of all cases of colorectal carcinoma present in an advanced and, therefore, incurable stage. For these patients, the development of new chemotherapeutic strategies is of central importance. Biochemical modulation of 5-fluorouracil (5-FU) has resulted in approximately a two-fold increase in activity of 5-FU. Recent preclinical investigations suggest that interferon can also modulate the activity of 5-FU and may result in enhanced response rates in patients. One of the critical mechanisms of resistance to 5-FU appears to be the acute induction in thymidylate synthase (TS) levels following therapy with inhibitors of this enzyme. This mechanism is based on a novel autoregulatory feedback pathway wherein the TS protein regulates its own translational efficiency. Regulatory function of the enzyme is dependent on its state of occupancy by either the physiologic ligands or inhibitors, including flouropyrimidines and antifolates. Ongoing efforts are directed towards utilizing knowledge of this protein/messenger RNA interaction for therapeutic benefit. Given the importance of TS, our laboratory has developed antibodies capable of quantitating the levels of this enzyme in fresh or paraffin-embedded tissues. Preliminary investigations suggest that the level of TS has prognostic importance in patients with rectal carcinoma and may be used to predict responsiveness to fluoropyrimidine agents. Novel strategies utilizing dual modulation of 5-FU with leucovurin and interferon are under investigation in both the advanced and adjuvant disease settings. Emerging mechanistic concepts regarding TS, along with the development of new, more potent inhibitors will hopefully result in future therapeutic gains.

AB - Approximately one-third of all cases of colorectal carcinoma present in an advanced and, therefore, incurable stage. For these patients, the development of new chemotherapeutic strategies is of central importance. Biochemical modulation of 5-fluorouracil (5-FU) has resulted in approximately a two-fold increase in activity of 5-FU. Recent preclinical investigations suggest that interferon can also modulate the activity of 5-FU and may result in enhanced response rates in patients. One of the critical mechanisms of resistance to 5-FU appears to be the acute induction in thymidylate synthase (TS) levels following therapy with inhibitors of this enzyme. This mechanism is based on a novel autoregulatory feedback pathway wherein the TS protein regulates its own translational efficiency. Regulatory function of the enzyme is dependent on its state of occupancy by either the physiologic ligands or inhibitors, including flouropyrimidines and antifolates. Ongoing efforts are directed towards utilizing knowledge of this protein/messenger RNA interaction for therapeutic benefit. Given the importance of TS, our laboratory has developed antibodies capable of quantitating the levels of this enzyme in fresh or paraffin-embedded tissues. Preliminary investigations suggest that the level of TS has prognostic importance in patients with rectal carcinoma and may be used to predict responsiveness to fluoropyrimidine agents. Novel strategies utilizing dual modulation of 5-FU with leucovurin and interferon are under investigation in both the advanced and adjuvant disease settings. Emerging mechanistic concepts regarding TS, along with the development of new, more potent inhibitors will hopefully result in future therapeutic gains.

KW - Antifolates

KW - Biochemical modulation

KW - Enzyme regulation

KW - Interferon

KW - Monoclonal antibodies

KW - Thymidylate synthase

KW - immunohistochemistry

UR - http://www.scopus.com/inward/record.url?scp=0030053929&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030053929&partnerID=8YFLogxK

U2 - 10.1002/stem.140041

DO - 10.1002/stem.140041

M3 - Review article

C2 - 8820950

AN - SCOPUS:0030053929

VL - 14

SP - 41

EP - 46

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 1

ER -