Corpus ID: 6234835

Biochemical studies on PT523, a potent nonpolyglutamatable antifolate, in cultured cells.

  title={Biochemical studies on PT523, a potent nonpolyglutamatable antifolate, in cultured cells.},
  author={M. Rhee and J. Galivan and J. Wright and A. Rosowsky},
  journal={Molecular pharmacology},
  volume={45 4},
Studies on the mode of action of PT523 [N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine], a potent nonpolyglutamatable antifolate, were carried out in sensitive and resistant H35 rat hepatoma cell lines in culture, to compare it with other antifolates, including three dihydrofolate reductase (DHFR) inhibitors, i.e., methotrexate (MTX), gamma-fluoro-MTX, and trimetrexate (TMQ), two thymidylate synthase inhibitors, i.e., N10-propargyl-5,8- dideazafolate (PDDF) and 2-desamino-2… Expand
Synthesis and Potent Antifolate Activity and Cytotoxicity of B-Ring Deaza Analogues of the Nonpolyglutamatable Dihydrofolate Reductase Inhibitor Nα-(4-Amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (PT523)
Six new B-ring analogues of the nonpolyglutamatable antifolate Nα-(4-amino-4-deoxypteroyl)-Nδ-hemiphthaloyl-l-ornithine (PT523, 3) were synthesized with a view to determining the effect ofExpand
Synthesis and Biological Activity of Nω-Hemiphthaloyl-α,ω-diaminoalkanoic Acid Analogues of Aminopterin and 3′,5-Dichloroaminopterin
Analogues of N~-(4-amino-4-deoxypteroyl)-N~-(hemiphthaloyl)-~-ornithine (PT523) with 3',5'dichloro substitution in the p-aminobenzoyl moiety or with one less or one more CH2 group in the amino acidExpand
The effect of side-chain, para-aminobenzoyl region, and B-ring modifications on dihydrofolate reductase binding, influx via the reduced folate carrier, and cytotoxicity of the potent nonpolyglutamatable antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L- ornithine.
Several of the second generation analogs of PT523 are more potent DHFR inhibitors and better RFC substrates than PT523 itself, and are more powerful inhibitors of tumor cell growth in culture. Expand
Antifolates can potentiate topoisomerase II inhibitors in vitro and in vivo
Overall, the antifolate/topoisomerase II inhibitor treatment combinations produced tumor growth delays that were apparently additive to greater than additive. Expand
Efficient utilization of the reduced folate carrier in CCRF-CEM human leukemic lymphoblasts by the potent antifolate N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-L- ornithine (PT523) and its B-ring analogues.
Results indicate that, in addition to their previously reported tight binding to dihydrofolate reductase, a property contributing to the high potency of PT523 and its B-ring analogs as inhibitors of tumor cell growth is their strong affinity for the RFC. Expand
Multiple mechanisms of resistance to polyglutamatable and lipophilic antifolates in mammalian cells: role of increased folylpolyglutamylation, expanded folate pools, and intralysosomal drug sequestration.
These multiple resistance factors collectively result in a prominent increase in folate accumulation, an expansion of the intracellular folylpolyglutamate pool, and abolishment of the cytotoxic activity of polyglutamatable and lipophilic antifolates. Expand
Development of Nonpolyglutamatable DHFR Inhibitors
The term “an-tifolate” or “antifol” has come to refer not only to inhibitors of DHFR but also to in-hibitors of other enzymes of one-carbon metabolism, especially thymidylate synthase (TS) and the two key players of de novo purine biosynthesis, GAR formyl-transferase and AICar formyltransferase. Expand
Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo
It is highlighted that modulation of dietary folate status can provide a basis within which the therapeutic effect of antifolates may be further improved. Expand
Loss of folylpoly‐γ‐glutamate synthetase activity is a dominant mechanism of resistance to polyglutamylation‐dependent novel antifolates in multiple human leukemia sublines
Reduced FPGS activity is a dominant mechanism of resistance to polyglutamylation‐dependent novel antifolates upon a high‐dose intermittent exposure schedule and offers a potentially promising treatment strategy in the overcoming of FPGs‐based anticancer drug resistance. Expand
Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis.
We determined the mechanisms of resistance of human CCRF-CEM leukemia cells to methotrexate (MTX) vs. those to six novel antifolates: the polyglutamatable thymidylate synthase (TS) inhibitors ZD1694,Expand