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 language | English |
|---|---|
| Pages (from-to) | 997-1001 |
| Number of pages | 5 |
| Journal | Biochemical Pharmacology |
| Volume | 37 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 15 1988 |
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ASJC Scopus subject areas
- Pharmacology
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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 journal › Article
}
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
VL - 37
SP - 997
EP - 1001
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 6
ER -