PMID- 8033293
OWN - NLM
STAT- MEDLINE
DCOM- 19940815
LR  - 20190830
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 34
IP  - 4
DP  - 1994
TI  - Novel pyrrolo[2,3-d]pyrimidine antifolate TNP-351: cytotoxic effect on 
      methotrexate-resistant CCRF-CEM cells and inhibition of transformylases of de 
      novo purine biosynthesis.
PG  - 273-9
AB  - N-[4-[3-(2,4-Diamino-7H-pyrrolo[2,3-d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic 
      acid (TNP-351), characterized by a pyrrolo[2,3-d]pyrimidine ring, is a novel 
      antifolate that exhibits potent antitumor activities against mammalian solid 
      tumors. The mechanism of action of TNP-351 was evaluated using some 
      methotrexate-resistant CCRF-CEM human lymphoblastic leukemia cell lines as well 
      as partially purified enzymes folylpolyglutamate synthetase (FPGS), 
      aminoimidazolecarboxamide ribonucleotide transformylase (AICARTFase), and 
      glycinamide ribonucleotide transformylase (GARTFase) from parent CCRF-CEM cells. 
      TNP-351 was found to inhibit the growth of L1210 and CCRF-CEM cells in culture, 
      with the doses effective against 50% of the cells (ED50 values) being 0.79 and 
      2.7 nM, respectively. The growth inhibition caused by TNF-351 was reversed by 
      leucovorin or a combination of hypoxanthine and thymidine. The 
      methotrexate-resistant CCRF-CEM cell line, which has an impaired methotrexate 
      transport, showed less resistance to TNP-351 than to methotrexate. TNP-351 was 
      also found to be an excellent substrate for FPGS with a Michaelis constant (Km) 
      of 1.45 microM and a maximum of velocity (Vmax) of 1,925 pmol h-1 mg-1. 
      Inhibitory activities of TNF-351-Gn (n = 1-6) for AICARTFase were found to be 
      significantly enhanced with increasing glutamyl chain length [inhibition 
      constants (Ki): G1, 52 microM; G6, 0.07 microM]. Neither TNP-351 nor its 
      polyglutamates were very strong inhibitors of GARTFase. These findings have 
      significant implications regarding the mechanism of action of TNP-351.
FAU - Itoh, F
AU  - Itoh F
AD  - Pharmaceutical Research Laboratories III, Takeda Chemical Industries, Ltd., 
      Osaka, Japan.
FAU - Russello, O
AU  - Russello O
FAU - Akimoto, H
AU  - Akimoto H
FAU - Beardsley, G P
AU  - Beardsley GP
LA  - eng
PT  - Journal Article
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Folic Acid Antagonists)
RN  - 125991-51-7 (TNP 351)
RN  - EC 2.1.2.- (Hydroxymethyl and Formyl Transferases)
RN  - EC 2.1.2.2 (Phosphoribosylglycinamide Formyltransferase)
RN  - EC 2.1.2.3 (Phosphoribosylaminoimidazolecarboxamide Formyltransferase)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 6.3.2.- (Peptide Synthases)
RN  - EC 6.3.2.17 (folylpolyglutamate synthetase)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Acyltransferases/antagonists & inhibitors
MH  - Animals
MH  - Cell Division/drug effects
MH  - Drug Resistance
MH  - Folic Acid Antagonists/metabolism/*pharmacology
MH  - Humans
MH  - *Hydroxymethyl and Formyl Transferases
MH  - Leukemia, Lymphoid/*drug therapy/enzymology
MH  - Methotrexate/*analogs & derivatives/metabolism/pharmacology/*therapeutic use
MH  - Mice
MH  - Peptide Synthases/metabolism
MH  - Phosphoribosylaminoimidazolecarboxamide Formyltransferase
MH  - Phosphoribosylglycinamide Formyltransferase
MH  - Tumor Cells, Cultured
EDAT- 1994/01/01 00:00
MHDA- 1994/01/01 00:01
CRDT- 1994/01/01 00:00
PHST- 1994/01/01 00:00 [pubmed]
PHST- 1994/01/01 00:01 [medline]
PHST- 1994/01/01 00:00 [entrez]
AID - 10.1007/BF00686032 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 1994;34(4):273-9. doi: 10.1007/BF00686032.