Selective in vitro inhibition of human MOLT-4 T lymphoblasts by the novel purine nucleoside phosphorylase inhibitor, CI-972.
CI-972 (2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3,2- d]pyrimidin-4-one monohydrochloride, monohydrate) is a competitive inhibitor of PNPase (E.C. 2.4.2.1., Ki = 0.83 microM) entering clinical trials as a T cell-selective immunosuppressive agent. Neither CI-972 (less than or equal to 50 microM) nor dGuo (less than or equal to 10 microM) inhibited [3H]Thd uptake by human MOLT-4 (T cell) or MGL-8 (B cell) lymphoblasts, but in the presence of 10 microM dGuo, the IC50 for CI-972 decreased to 3.0 microM for MOLT-4 but remained at greater than 50 microM for MGL-8. Inhibition of MOLT-4 growth was associated with an increase in dGTP that was dependent on CI-972 concentration and inhibited by 2'-deoxycytidine. Growth could not be restored by hypoxanthine or adenine. No alterations in GTP pools were noted in MOLT-4, and neither GTP nor dGTP were altered in MGL-8.
Gilbertsen
R B
RB
Department of Immunopathology, Warner-Lambert Company, Ann Arbor, MI 48105.
Dong
M K
MK
Kossarek
L M
LM
Sircar
J C
JC
Kostlan
C R
CR
Conroy
M C
MC
D000225:Adenine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D003841:Deoxycytidine / Q000494:pharmacology; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D007700:Kinetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D013601:T-Lymphocytes; D013876:Thiophenes / Q000494:pharmacology*
D003848:Deoxyguanine Nucleotides; D007042:Hypoxanthines; D011743:Pyrimidines; D013876:Thiophenes; D003841:Deoxycytidine; C070377:CI 972; D019271:Hypoxanthine; D006160:Guanosine Triphosphate; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase; D000225:Adenine