Uptake and metabolism of 5,8-dideazaisofolic acid in human colon carcinoma cells

Alberto F. Sobrero, John J. McGuire, Joseph R. Bertino

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The uptake and metabolism of radiolabeled 5,8-dideazaisofolic acid (IAHQ) (N-[p-[(2-amino-4-hydroxy-6-quinazolinyl)] amino]methylbenzoyl]-l-glutamic acid), a new antifol targeted to thymidylate synthase, has been investigated in the human colon adenocarcinoma cell line HCT-8. [3H]IAHQ uptake was very slow, requiring days to achieve the intracellular level achieved in minutes by [3H]methotrexate. This slow transport of IAHQ was consistent with the long exposures required to achieve cytotoxicity. Intracellular [3H]IAHQ was converted in a concentration-dependent manner to polygamma-glutamate derivatives containing between two and four additional glutamate residues. These results are consistent with our hypothesis that IAHQ is a "pro-drug" which must be converted to polyglutamate derivatives before it is a sufficiently potent inhibitor of thymidylate synthase to induce a pyrimidineless state and cell death.

Original languageEnglish
Pages (from-to)997-1001
Number of pages5
JournalBiochemical Pharmacology
Volume37
Issue number6
DOIs
Publication statusPublished - Mar 15 1988

Fingerprint

Metabolism
Colon
Cells
Carcinoma
Glutamic Acid
Thymidylate Synthase
Polyglutamic Acid
Derivatives
Prodrugs
Cell death
Cytotoxicity
Methotrexate
5,8-dideazaisofolic acid
Adenocarcinoma
Cell Death
Cell Line

ASJC Scopus subject areas

  • Pharmacology

Cite this

Uptake and metabolism of 5,8-dideazaisofolic acid in human colon carcinoma cells. / Sobrero, Alberto F.; McGuire, John J.; Bertino, Joseph R.

In: Biochemical Pharmacology, Vol. 37, No. 6, 15.03.1988, p. 997-1001.

Research output: Contribution to journalArticle

Sobrero, Alberto F. ; McGuire, John J. ; Bertino, Joseph R. / Uptake and metabolism of 5,8-dideazaisofolic acid in human colon carcinoma cells. In: Biochemical Pharmacology. 1988 ; Vol. 37, No. 6. pp. 997-1001.
@article{82e305c88c7d47dcbbf5d1d64625777f,
title = "Uptake and metabolism of 5,8-dideazaisofolic acid in human colon carcinoma cells",
abstract = "The uptake and metabolism of radiolabeled 5,8-dideazaisofolic acid (IAHQ) (N-[p-[(2-amino-4-hydroxy-6-quinazolinyl)] amino]methylbenzoyl]-l-glutamic acid), a new antifol targeted to thymidylate synthase, has been investigated in the human colon adenocarcinoma cell line HCT-8. [3H]IAHQ uptake was very slow, requiring days to achieve the intracellular level achieved in minutes by [3H]methotrexate. This slow transport of IAHQ was consistent with the long exposures required to achieve cytotoxicity. Intracellular [3H]IAHQ was converted in a concentration-dependent manner to polygamma-glutamate derivatives containing between two and four additional glutamate residues. These results are consistent with our hypothesis that IAHQ is a {"}pro-drug{"} which must be converted to polyglutamate derivatives before it is a sufficiently potent inhibitor of thymidylate synthase to induce a pyrimidineless state and cell death.",
author = "Sobrero, {Alberto F.} and McGuire, {John J.} and Bertino, {Joseph R.}",
year = "1988",
month = "3",
day = "15",
doi = "10.1016/0006-2952(88)90500-X",
language = "English",
volume = "37",
pages = "997--1001",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Uptake and metabolism of 5,8-dideazaisofolic acid in human colon carcinoma cells

AU - Sobrero, Alberto F.

AU - McGuire, John J.

AU - Bertino, Joseph R.

PY - 1988/3/15

Y1 - 1988/3/15

N2 - The uptake and metabolism of radiolabeled 5,8-dideazaisofolic acid (IAHQ) (N-[p-[(2-amino-4-hydroxy-6-quinazolinyl)] amino]methylbenzoyl]-l-glutamic acid), a new antifol targeted to thymidylate synthase, has been investigated in the human colon adenocarcinoma cell line HCT-8. [3H]IAHQ uptake was very slow, requiring days to achieve the intracellular level achieved in minutes by [3H]methotrexate. This slow transport of IAHQ was consistent with the long exposures required to achieve cytotoxicity. Intracellular [3H]IAHQ was converted in a concentration-dependent manner to polygamma-glutamate derivatives containing between two and four additional glutamate residues. These results are consistent with our hypothesis that IAHQ is a "pro-drug" which must be converted to polyglutamate derivatives before it is a sufficiently potent inhibitor of thymidylate synthase to induce a pyrimidineless state and cell death.

AB - The uptake and metabolism of radiolabeled 5,8-dideazaisofolic acid (IAHQ) (N-[p-[(2-amino-4-hydroxy-6-quinazolinyl)] amino]methylbenzoyl]-l-glutamic acid), a new antifol targeted to thymidylate synthase, has been investigated in the human colon adenocarcinoma cell line HCT-8. [3H]IAHQ uptake was very slow, requiring days to achieve the intracellular level achieved in minutes by [3H]methotrexate. This slow transport of IAHQ was consistent with the long exposures required to achieve cytotoxicity. Intracellular [3H]IAHQ was converted in a concentration-dependent manner to polygamma-glutamate derivatives containing between two and four additional glutamate residues. These results are consistent with our hypothesis that IAHQ is a "pro-drug" which must be converted to polyglutamate derivatives before it is a sufficiently potent inhibitor of thymidylate synthase to induce a pyrimidineless state and cell death.

UR - http://www.scopus.com/inward/record.url?scp=0023831078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023831078&partnerID=8YFLogxK

U2 - 10.1016/0006-2952(88)90500-X

DO - 10.1016/0006-2952(88)90500-X

M3 - Article

C2 - 2451526

AN - SCOPUS:0023831078

VL - 37

SP - 997

EP - 1001

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 6

ER -