[Show abstract][Hide abstract] ABSTRACT: Type 4 cyclic AMP (cAMP) phosphodiesterase (PDE4) inhibitors, a class of compounds in clinical development that activate cAMP-mediated signaling by inhibiting cAMP catabolism, offer a feasible means by which to potentiate glucocorticoid-mediated apoptosis in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). In this study, we show that PDE4 inhibitors up-regulate glucocorticoid receptor (GRalpha) transcript levels in B-CLL cells but not T-CLL cells or Sezary cells or normal circulating T cells, B cells, monocytes, or neutrophils. Because GRalpha transcript half-life does not vary in CLL cells treated with the prototypic PDE4 inhibitor rolipram, the 4-fold increase in GRalpha mRNA levels observed within 4 h of rolipram treatment seems to result from an increase in GRalpha transcription. Rolipram treatment increases levels of transcripts derived from the 1A3 promoter to a greater extent than the 1B promoter. Treatment of B-CLL cells with two other PDE4 inhibitors currently in clinical development also augments GR transcript levels and glucocorticoid-mediated apoptosis. Washout studies show that simultaneous treatment with both drug classes irreversibly augments apoptosis over the same time frame that GR up-regulation occurs. Although treatment of B-CLL cells with glucocorticoids reduces basal GRalpha transcript levels in a dose-related manner, cotreatment with rolipram maintained GRalpha transcript levels above baseline. Our results suggest that as a result of their unusual sensitivity to PDE4 inhibitor-mediated up-regulation of GRalpha expression, treatment of B-CLL patients with combined PDE4 inhibitor/glucocorticoid therapy may be of therapeutic benefit in this disease.
Clinical Cancer Research 09/2007; 13(16):4920-7. DOI:10.1158/1078-0432.CCR-07-0276 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rituximab is a humanized monoclonal antibody directed against CD20-positive B cells and originally developed for the treatment of non-Hodgkins lymphoma. We report a case of severe mucous membrane pemphigoid responsive to rituximab infusions. The clinical presentation, etiology, and management options for mucous membrane pemphigoid are also discussed.
Journal of drugs in dermatology: JDD 08/2007; 6(7):731-2. · 1.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mycophenolate mofetil is commonly used as a steroid-sparing agent effective in the management of erythema nodosum, idiopathic nodular panniculitis (Pfiefer-Weber-Christian disease), bullous pemphigoid, pemphigus vulgaris, and psoriasis. We report a case of nodular vasculitis responsive to mycophenolate mofetil. The clinical presentation, etiology, and management options for nodular vasculitis are discussed.
Journal of drugs in dermatology: JDD 01/2006; 5(10):992-3. · 1.45 Impact Factor