Antiangiogenic Activity of Alofanib, an Allosteric Inhibitor of Fibroblast Growth Factor Receptor 2.

Alofanib is a potential allosteric inhibitor of FGFR2 used in oncology. The inhibitor blocks the extracellular part of the receptor and prevents its binding with the ligand. Alofanib suppressed proliferation of endothelial cells, their migration activity, and ability to form vessellike structures in vitro and significantly decreased the number of microvessels in Matrigel implant and in ovarian cancer (SKOV-3) xenograft in vivo. The results indicate that Alofanib can inhibit angiogenesis.

[Synthesis and biological properties of 3,5-cyclophosphates- and -amidophosphates of 1,2-O-alkylydene-6-deoxy-6-halogeno-alpha -D-glucofuranoses]. / Sintez i biologicheskie svoistva 3,5-tsiklofosfatov i amidofosfatov 6-galoid-6-dezoksi-1,2-O-alkiliden-alpha-D-gliukofuranoz.

3,5-Cyclic phosphates and phosphoramides of 6-halogenated glucofuranoses were synthesized via interaction of 3,5,6-bicyclophosphites of 1,2-O-alkylidene-alpha-D-glucofuranoses with halogens (followed by treatment with nucleophilic reagents) and N-chloroamines. 3,5-Cyclic trans-dibutylphosphoramides of 6-chloro-6-deoxy-1,2-O-isopropylidene- and 6-chloro-6-deoxy-(R)-(2,2,2)-trichloroethylidene)-alpha-D-glucofuranoses were shown to possess antiproliferative activity against CaOv human ovarian carcinoma cells in vitro (CE50 of approximately 10(-5) M). Cyclic trans-dibutylphosphoramide of 6-chloro-6-deoxy-1,2,-O-isopropylidene-alpha-D-glucofuranose also displayed marked antitumor effect on P-388 transplantable murine leukemia in vivo (the maximum increase in life span of 100% was reached at the quintuple injection of 100 mg/kg daily).

[Disruption of DNA synthesis and structure of mouse L1210 leukemia cells, sensitive and resistant to 1-methyl-1 nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea in vivo]. / Narusheniia v sinteze i strukture DNK kletok leikoza L1210 myshei, chuvstvitel'nykh i rezistentnykh k 1-metil-1-nitrozomochevine i 1,3-bis(2-khlorétil)-1-nitrozomochevine in vivo.

Leukemia L1210 cells with acquired resistance to 1-methyl-1-nitrosourea (MNU) (L1210/MNU) and 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (L1210/BCNU) were developed from leukemia L1210 cells sensitive to these drugs (L1210/0). The modal chromosome number of leukemia L1210/MNU and L1210/BCNU cells increases from 40 (L1210/0) to 41. It was shown that in leukemia L1210/MNU cells the inhibition of DNA synthesis after MNU administration in a therapeutic dose (80 mg/kg) is lasted within 24 hours, while that in leukemia L1210/0 cell--within 96 hours. After administration of BCNU (20 mg/kg) inhibition of DNA synthesis in leukemia L1210/BCNU cells reached of 50% of control in comparison with practically complete inhibition of DNA synthesis in leukemia L1210/0 cells. Centrifugation on alkaline sucrose density gradients revealed no differences in the rate of sedimentation of leukemia L1210/0, L1210/MNU and L1210/BCNU cell lysates. After 1 hour treatment with MNU of mice bearing L1210/MNU and L1210/0 leukemia cells single-strand breaks in DNA were determined. After 4 hours these strand-breaks retained in leukemia L1210/0 cells, but were eliminated in leukemia L1210/MNU cells. Administration of BCNU to mice with leukemia L1210/0 and L1210/BCNU cells resulted in both cases in the production of DNA aggregates. There is no complete cross-resistance between MNU and BCNU which allows a substitution of these drugs providing for the increase in their therapeutic efficiency.