Kinetic characterization of the inhibition of protein tyrosine phosphatase-1B by Vanadyl (VO2+) chelates.

Protein tyrosine phosphatases (PTPases) are a prominent focus of drug design studies because of their roles in homeostasis and disorders of metabolism. These studies have met with little success because (1) virtually all inhibitors hitherto exhibit only competitive behavior and (2) a consensus sequence H/V-C-X5-R-S/T characterizes the active sites of PTPases, leading to low specificity of active site directed inhibitors. With protein tyrosine phosphatase-1B (PTP1B) identifed as the target enzyme of the vanadyl (VO2+) chelate bis(acetylacetonato)oxidovanadium(IV) [VO(acac)2] in 3T3-L1 adipocytes [Ou et al. J Biol Inorg Chem 10: 874-886, 2005], we compared the inhibition of PTP1B by VO(acac)2 with other VO2+-chelates, namely, bis(2-ethyl-maltolato)oxidovanadium(IV) [VO(Et-malto)2] and bis(3-hydroxy-2-methyl-4(1H)pyridinonato)oxidovanadium(IV) [VO(mpp)2] under steady-state conditions, using the soluble portion of the recombinant human enzyme (residues 1-321). Our results differed from those of previous investigations because we compared inhibition in the presence of the nonspecific substrate p-nitrophenylphosphate and the phosphotyrosine-containing undecapeptide DADEpYLIPQQG mimicking residues 988-998 of the epidermal growth factor receptor, a relevant, natural substrate. While VO(Et-malto)2 acts only as a noncompetitive inhibitor in the presence of either subtrate, VO(acac)2 exhibits classical uncompetitive inhibition in the presence of DADEpYLIPQQG but only apparent competitive inhibition with p-nitrophenylphosphate as substrate. Because uncompetitive inhibitors are more potent pharmacologically than competitive inhibitors, structural characterization of the site of uncompetitive binding of VO(acac)2 may provide a new direction for design of inhibitors for therapeutic purposes. Our results suggest also that the true behavior of other inhibitors may have been masked when assayed with only p-nitrophenylphosphate as substrate.

Extensive Cutaneous T-Cell Lymphoma of the Feet Treated with High-Dose-Rate Brachytherapy and External Beam Radiation.

Cutaneous T-cell lymphoma (CTCL) is a chronic, debilitating disease that has a severe impact on quality of life. We present a patient with multiple CTCL lesions on the bilateral feet, which impaired his ability to ambulate. His lesions on both feet were successfully treated with a total of 8 Gy in two fractions via high-dose-rate surface brachytherapy using the Freiburg Flap applicator. The deeper aspects of the bulkier lesions on the left foot were boosted with electron beam therapy. The radiation therapy was well tolerated, and the patient was able to regain his mobility after completing radiation therapy. To our knowledge, there are few reports utilizing brachytherapy in treating CTCL. Our case describes treatment of larger, more extensive CTCL lesions than previously reported.

Unusual clinical presentation of cutaneous angiosarcoma masquerading as eczema: a case report and review of the literature.

An unusual case of cutaneous angiosarcoma clinically mimicking eczema is described. A 98-year-old Caucasian male presented with a 6-month history of a flesh-colored, subcutaneous nodule on his left forehead with contralateral facial erythema and scaling that had been previously diagnosed as eczema. Despite treatments with topical steroids and moisturizers, the condition did not resolve. At our clinic, excisional biopsy of the forehead lesion and scouting biopsies from the contralateral cheek were performed which revealed cutaneous angiosarcoma. The described case illustrates that dermatitis-like features should be considered as a rare clinical manifestation of cutaneous angiosarcoma. It also demonstrates that these lesions may respond well to radiotherapy as a single modality.