Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Hodgkin Disease/drug therapy , Immunoconjugates/therapeutic use , Salvage Therapy , Adult , Biopsy , Bleomycin/administration & dosage , Brentuximab Vedotin , Dacarbazine/administration & dosage , Doxorubicin/administration & dosage , Female , Hodgkin Disease/immunology , Hodgkin Disease/pathology , Humans , Lymph Nodes/drug effects , Lymph Nodes/immunology , Lymph Nodes/pathology , Treatment Outcome , Vinblastine/administration & dosageABSTRACT
A 72-year-old woman presented with dyspnea and lower extremity edema. Extreme lymphocytosis, cytopenia, and splenomegaly were found, and she was diagnosed with B-prolymphocytic leukemia. Following the first dose of therapy with bendamustine, the patient developed severe generalized maculopapular rash, which subsequently progressed to exuberant, non-blanching palpable purpura with hemorrhagic plaques suspicious for leukocytoclastic vasculitis. These events coincided with severe chemotherapy-induced neutropenia and thrombocytopenia, but there were no clinical symptoms of infection. Skin punch biopsy revealed perivascular and diffuse upper dermal lymphocytic infiltrate with eosinophils and marked erythrocyte extravasation consistent with a purpuric drug exanthem. The patient was treated with steroids, with complete resolution of the findings. This new form of cutaneous toxicity of bendamustine is presented along with a review of previous experience with the drug.
Subject(s)
Antineoplastic Agents, Alkylating/adverse effects , Drug Eruptions/pathology , Exanthema/chemically induced , Leukemia, Prolymphocytic, B-Cell/complications , Nitrogen Mustard Compounds/adverse effects , Purpura/chemically induced , Aged , Antineoplastic Agents, Alkylating/therapeutic use , Bendamustine Hydrochloride , Biopsy , Drug Eruptions/drug therapy , Exanthema/drug therapy , Exanthema/pathology , Female , Humans , Leukemia, Prolymphocytic, B-Cell/drug therapy , Nitrogen Mustard Compounds/therapeutic use , Purpura/drug therapy , Purpura/pathology , Skin/pathology , Treatment OutcomeABSTRACT
Tissue transglutaminase (TG2) is a transpeptidase involved in protein cross-linking through generation of ε-(γ-glutamyl)lysine isopeptide bonds. It also promotes cell adhesion through interaction with fibronectin and facilitates formation of fibronectin-integrin complexes. This interaction is involved in tumor cell adhesion to the matrix and in the process of tumor dissemination. Its inhibition by small molecules may therefore be useful in blocking metastasis. To that end, we screened more than 800,000 compounds following an in silico docking approach targeting two distinct cavities in the vicinity of the fibronectin-binding site on TG2. A total of 120 compounds were acquired and tested in cell culture-based assays for inhibition of ovarian tumor cell adhesion and proliferation. Seven compounds showed more than 50% inhibition of cell adhesion at a concentration of 25 µmol/L. A follow-up fluorescence polarization study revealed that one compound in particular (ITP-79) inhibited binding of a TG2 peptide to a 42-kDa fragment of fibronectin in a dose-dependent manner. This inhibition was confirmed in cancer cells by coimmunoprecipitation. A competition assay with surface plasmon resonance showed that ITP-79 modulated binding of TG2 to fibronectin. Direct binding of compounds that inhibited adhesion to TG2 were examined with differential scanning fluorimetry, which measures the effect of the compound on the melting temperature of the target. Two compounds, including ITP-79, reduced TG2 stabilization, mimicking the effects of GTP, a known negative allosteric regulator of TG2 enzymatic function. This suggests a potential allosteric mechanism for the compound in light of its distal target site.
