OBJECTIVESome pyrimidine analogues have been found to induce differentiation of several human myeloid leukemia cells. Newly synthesized heterocyclic pyrimidine derivatives promote neurite outgrowth and survival in neuronal cell lines. In this study, the growth-inhibiting and differentiation-inducing effects of these pyrimidine derivatives on human myeloid leukemia cells were examined.MATERIALS AND METHODSSeveral myeloid leukemia cells were cultured with novel heterocyclic pyrimidine derivatives. Cell differentiation was determined by nitroblue tetrazolium-reducing activity, morphologic changes, expression of CD11b, lysozyme activity, and hemoglobin production.RESULTSMS-430 (2-piperidino-5,6-dihydro-7-methyl-6-oxo (7H) pyrrolo [2,3-d] pyrimidine maleate) effectively induced HL-60 cells into mature granulocytes. MS-430 activated the mitogen-activated protein kinase (MAPK) of the cells before causing granulocytic differentiation. MAPK activation was necessary for MS-430-induced differentiation, because PD98059, an inhibitor of MAPK kinase, suppressed the differentiation induced by MS-430. MS-430 also induced monocytic differentiation of THP-1, P39/Tsu, and P31/Fuj leukemia cells, but did not affect erythroid differentiation of K562 or HEL cells.CONCLUSIONSMS-430 potently induces differentiation of some myelomonocytic leukemia cells. This novel synthesized pyrimidine compound shows promise as a therapeutic agent for treatment of leukemia and as a neurotrophic drug.

01 Jan 1999·Restorative neurology and neuroscience

The effect of neurotrophic pyrimidine heterocyclic compounds, MS-818 and MS-430, on the regeneration of injured peripheral nerves.

Article

Author: Shinomiya, Kenichi ; Awaya, Akira ; Itoh, Soichiro ; Samejima, Hirotake

The effects of pyrimidine heterocyclic compounds (MS-818 and MS-430) on nerve regeneration were evaluated using the cut-and-suture model of the right sciatic nerve of Wistar rats. After surgery, 1 or 5 mg/kg/day of MS-818 or MS-430 was intraperitoneally administered for 21 days. Control rats received the same surgery, but were administered saline instead of a drug. Each week from week 2, evoked muscle action potentials were recorded on the calf muscle to compare the ratio of latency and amplitude between tbe experimental and non-treated side. The specimens were taken from the tibial nerve for light microscopic observation; and the diameter, density and % axon area of myelinated axons were evaluated. Tbe results of EMG and histology suggest that administration of MS-818 is more effective than that of MS-430 and that administration of 5 mg/kg/day has a higher promoting effect than that of 1 mg/kg/day for sprouting and elongation of the severed nerve. These new neurotrophic pyrimidine compounds may be a group of possible substances effective in facilitating nerve regeneration.

01 Nov 1998·General Pharmacology: The Vascular System

Increase of Nerve Regeneration Capacity by New Neurotrophic Pyrimidine Derivative MS-430

Article

Author: Mitsuo Ochi ; Yoshikazu Ikuta ; Masayuki Noda ; Akira Awaya

1. We studied whether a new neurotrophic pyrimidine compound, MS-430, can increase the regeneration length of the transected sciatic nerve in a silicone chamber gap of 14 mm. 2. The average length of regenerated myelinated axons in ten cases was 9.0+/-0 mm in the control group, 2.8+/-1.9 mm in the 1 mg/kg/day of the MS-430 group and 5.0+/-5.1 mm in the 3 mg/kg/day of the MS-430 group, indicating that the average length was significantly larger in the 3-mg group than that in the control group (P<0.05). 3. The results clearly showed that the MS-430 has promoting effects on nerve regeneration.

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Cognition Disorders	Preclinical	JP	Nihon Schering KK	-

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