| Autor: |
Gilbertsen RB; Department of Immunopathology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105., Dong MK, Wilburn DJ, Kossarek LM, Sircar JC, Kostlan CR, Conroy MC |
| Jazyk: |
angličtina |
| Zdroj: |
Advances in experimental medicine and biology [Adv Exp Med Biol] 1991; Vol. 309A, pp. 41-4. |
| DOI: |
10.1007/978-1-4899-2638-8_8 |
| Abstrakt: |
CI-972 (2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4H-pyrrolo[3, 2-d]pyrimidin-4-one monohydrochloride, monohydrate) is a novel inhibitor of PNP (Ki = 0.83 microM) under development as a T cell-selective immunosuppressive agent. CI-972 inhibited proliferation (3H-thymidine uptake) of human MOLT-4 (T cell) but not MGL-8 (B cell) lymphoblasts with respective IC50s of 3.0 and greater than 50 microM when tested with 10 microM 2'-deoxyguanosine. Without addition of exogenous 2'-deoxyguanosine, CI-972 was not inhibitory to any human T or B lymphoblastoid cell line tested. 2'-Deoxycytidine (10 microM), but not hypoxanthine or adenine, restored MOLT-4 cell growth. Inhibition of 3H-thymidine uptake in MOLT-4 cells correlated with accumulation of dGTP, while alterations in guanine nucleotides were not observed. 2'-Deoxycytidine (10 microM) also blocked dGTP accumulation in MOLT-4 cells. CI-972 showed activity in vivo over a broad dose range: At 5-150 mg/kg p.o., CI-972 produced dose-dependent elevation of plasma inosine one hr after administration to rats (mean maximum of 2.62 vs. 0.06 microM in controls). Guanosine was also significantly elevated in a concentration-dependent manner, although the effect was not as impressive. Plasma nucleosides remained statistically-significantly elevated for up to four hr following a single oral dose of CI-972. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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