Reference

Inhibition of phorbol-ester-induced adhesion of differentiating human myeloid leukemic cells by pentamidine-isethionate

Inhibition of phorbol-ester-induced adhesion of differentiating human myeloid leukemic cells by pentamidine-isethionate. Klemes, Yoel; Kidron, Miriam; Mayer, Michael; Fibach, Eitan (Everyman's Univ., Tel Aviv-Jaffa 61932, Israel). Differentiation (Berlin), 27(2), 141-5 (English) 1984. CODEN: DFFNAW. ISSN: 0301-4681. DOCUMENT TYPE: Journal CA Section: 4 (Toxicology) Human myeloid leukemia cells can be induced to differentiate into macrophage-like cells by various phorbol esters, particular TPA [16561-29-8]. In this study, the effect of several known protease inhibitors on TPA-induced differentiation of human acute promyelocytic leukemia cells (line HL-60) was tested. Among the tested compds. only pentamidine isethionate (PI) [140-64-7], an inhibitor of trypsinlike enzymes, prevented 1 early marker of differentiation, cell adherence to plastic and glass surfaces. However, PI failed to affect other markers of differentiation and did not inhibit readherence of scraped and resuspended TPA-treated cells. Exposure to TPA resulted in a decrease in the cellular alk. proteolytic activity and an increase in the acid proteolytic activity. PI further inhibited the residual activity of the alk. protease in the 36,000-g pellet fraction of the TPA-treated cells, but did not reduce this activity in control cells. Thus, on the basis of the differential effects of PI, the emergence of differentiation markers in HL-60 cells following exposure to TPA is independent of the induction of adherence.

Complex inhibition of thymidylate synthetase by aromatic diamidines: evidence for both rapid, freely reversible and slowly progressive, nonequilibrium inhibition

Complex inhibition of thymidylate synthetase by aromatic diamidines: evidence for both rapid, freely reversible and slowly progressive, nonequilibrium inhibition. Kaplan, Henry G.; Myers, Charles E. (Natl. Cancer Inst., NIH, Bethesda, Md., USA). J. Pharmacol. Exp. Ther., 201(3), 554-63 (English) 1977. CODEN: JPETAB. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) The activity of pentamidine diisethionate (I) [140-64-7] and its analogs propamidine diisethionate (II) [140-63-6] and stilbamidine diisethionate (III) [140-59-0] against dihydrfolate reductase [9002-03-3] and thymidylatesynthetase [9031-61-2] from Lactobacillus casei, Crithidia fasciulata and from human lymphatic leukemia cells was examd. Detailed studies of I with L. casei thymidylate synthetase revealed a complex mechanism of rapidly reversible inhibition. Preincubation in the absence of dUMP and N5, N10-methylene-H4 folate revealed a temp.-sensitive, biphasic, slowly progressive increase of inhibition. Inhibition was slowly reversible with 40% reactivation of enzyme from the enzyme-inhibitor complex after 24 h at 37° in the presence of high concns. of dUMP. The slowly progressive increase in inhibition was antagonized by each substrate according to the affinity of that substrate for the enzyme. Although benzamidine and isethionic acid did not inhibit thymidylate synthetase, II and III were both inhibitors, with increasing inhibitory activity correlated with increasing mol. length. No inhibition of dihydrofolate reductase by I was demonstrated with any of the 3 species over a broad range of conditions. Inhibition of thymidylate synthetase may play a role in the inhibition of cell growth by aromatic diamidines.