Jon C. Nixon

Platelet-derived growth factor and its receptor in blood cell differentiation and neoplasia

Platelet‐derived growth factor (PDGF) is a family of dimeric protein molecules synthesized by differentiated, non‐dividing and proliferating blood cells. Experimental findings indicate that PDGF is involved in development and/or maintenance of physiological functions of certain normal blood cells. Also, PDGF synthesis correlates with certain blood cell proliferative diseases caused either spontaneously or associated with viral infection. There is increasing evidence that the diverse effects of PDGF in both normal and abnormal physiological functions of blood cells may be regulated at the level of its receptor. New experimental findings are discussed relating to PDGF receptors in normal leukemic, and virally‐infected human cells of myeloid and lymphocytic lineages. At specific developmental stages this regulation may take the form of PDGF and its receptor being expressed or co‐expressed; the unmodified or modified form of receptor that specifically interacts with PDGF; the cellular site at which the PDGF‐receptor interacts with its ligand; and co‐expression of the PDGF‐receptor with other receptors associated with specific cell lineage or functions. Elucidation of events involved in synthesis, processing, and interactions of PDGF isoforms and their respective receptors will enable us to develop pharmacological means that may either interfere with, or enhance these desired blood cell functions. This review focuses on PDGF and its receptor in human blood cell differentiation and neoplasia.

Characterization of the In Vitro Anti-inflammatory Activity of AL-5898 and Related Benzopyranyl Esters and Amides

Selected ester- (AL-5898 and AL-8417) and amide-linked benzopyran analogues (AL-7538 and AL-12615) were evaluated in vitro for their ability to inhibit key enzymes/processes of the inflammatory response. AL-7538 and AL-12615 exhibited weak intrinsic cyclooxygenase inhibitory activity (IC50 = 13 μM, 37 μM). In contrast, 5-HETE and LTB4 synthesis in A23187-stimulated neutrophils was effectively inhibited by both ester and amide analogs (IC50 = 2–3 μM). While there was some indication for differing sensitivities among benzopyran esters and amides in the suppression of cytokine synthesis in stimulated U-937 cells, there appeared to be no great discrimination when assessing their effect on U-937 cell adhesion to IL-1β activated HMVEC-L cells. Inhibition of cell adhesion was concentration-dependent, with IC50 values ranging between 18 μM and 30 μM for AL-5898. Concentration-dependent inhibition of inflammatory cytokine production (i.e., IL-1β, TNF-α, GM-CSF and IL-6) was also apparent in LPS-stimulated, cultured PBMC as well as in PMA/A23187 activated U-937 cells monitoring the synthesis of IL-1β, IL-8, TNF-α, and MCP-1. Notably, the hydrolysis products of the benzopyranyl ester, AL-5692 and (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, were devoid of pharmacological activity when assessed for inhibition of monocyte adhesion or IL-1β synthesis. Collectively, our data demonstrate the unique in vitro polypharmacology of a novel series of benzopyran analogs that suppress pivotal enzymes and processes in the inflammatory response.