ABSTRACT
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Aniline Compounds/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Phthalazines/chemical synthesis , Pyridines , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Growth Factor/antagonists & inhibitors , Administration, Oral , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Biological Availability , CHO Cells , Cell Line , Cricetinae , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Mice , Models, Molecular , Neoplasms/blood supply , Neovascularization, Pathologic , Phosphorylation , Phthalazines/chemistry , Phthalazines/pharmacokinetics , Phthalazines/pharmacology , Proto-Oncogene Proteins/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Growth Factor/genetics , Receptors, Vascular Endothelial Growth Factor , Structure-Activity Relationship , Transfection , Vascular Endothelial Growth Factor Receptor-1ABSTRACT
BACKGROUND: In Spring 1992, an epidemic outbreak of papular and follicular rashes caused by a new line of cosmetics occurred throughout Switzerland. OBJECTIVE: Epidemiological and clinical data were collected in order to identify the offending agent and to specify the pathophysiological mechanisms. METHODS: The data concerning 263 patients seen by dermatologists plus 642 additional cases directly reported by consumers to the manufacturer were analyzed. Seventy-seven patients were patch-tested, 26 extensively, and 15 performed a repeated open application test for a duration of 4 weeks. Control patch and use tests were performed in 73 and 25 patients, respectively. The results were analyzed statistically. In addition, 12 skin biopsies were performed for histological examination. Biochemical studies on the cosmetics (final products and offending ingredient) supplemented the clinical studies. RESULTS: The lesions were mainly papular and follicular, widely distributed, with pronounced pruritus, which was aggravated by sweating or heat exposure, and were long lasting. In a few cases, the papules were located on intensely erythematous, well-defined plaques, suggesting irritation rather than allergy. Both immediate and delayed onsets of the lesions were observed. Skin biopsies showed signs of folliculitis and perifolliculitis with little alteration of the interfollicular epidermis. Patch and use testing disclosed vitamin E linoleate (a mixture of tocopheryl esters, mainly tocopheryl linoleate) as the offending agent. An in vitro time-dependent formation of oxidative products under storage or oxidation-stimulating conditions was observed. CONCLUSION: Though vitamin E esters have been widely and safely used for decades in dermatological preparations and in cosmetics, vitamin E linoleate was the cause of about 1,000 cases of unusual papular mainly follicular contact dermatitis. Oxidized vitamin E derivatives could act in vivo as haptens and/or irritants, possibly with synergistic effects.
