Biomedical subjects

Claudia Drewniok

Publications and source records attributed to Claudia Drewniok.

5 recordsLinked to original sources

PubMed2004

Molecular interactions of B-CAM (basal-cell adhesion molecule) and laminin in epithelial skin cancer.

Molecular events underlying the progression of malignant tumors through the surrounding tissue are largely mediated by membrane-bound adhesion molecules. Basal-cell adhesion molecule (B-CAM), a 90-kDa laminin receptor of the immunoglobulin superfamily, is induced in some epithelial malignancies. Its function in these tumors, however, still remains obscure. We demonstrated that expression of B-CAM is very weak, if detectable at all, in normal epidermis but is strongly induced in both basal cell carcinomas and squamous cell carcinomas of the skin, and most pronounced at the basal surface of the tumor nests. Interestingly, the only known B-CAM ligand, laminin, was markedly upregulated within corresponding microanatomical sites surrounding the tumor nests, suggesting that both molecules may interact there. Consistent with this hypothesis, we were able to directly demonstrate binding of a B-CAM/Fc chimeric molecule to the peritumoral stroma in situ. Finally, in proof-of-principle experiments, human B-CAM was overexpressed both in murine and in human fibroblasts. The haptotactic migration of these novel B-CAM+ cell populations on a laminin matrix was significantly increased (P = 0.02) as compared to mock-transfected cells when integrin-mediated adhesion was blocked by chelation of divalent cations. Thus, our findings provide the first direct experimental evidence that interactions of B-CAM and laminin may be involved in progression of epithelial skin tumors.

Animals↗

PubMed2004

Death receptor-independent apoptosis in malignant melanoma induced by the small-molecule immune response modifier imiquimod.

Bypassing molecular mechanisms of apoptosis deficiency may be of great utility for the successful treatment of malignant tumors. We have discovered that imiquimod, a small-molecule immunomodulator, exerts rather tumor-selective direct pro-apoptotic activity in vivo and in vitro towards cutaneous metastases of malignant melanoma, an aggressive skin tumor. This pro-apoptotic activity was not detectable with resiquimod, a closely related structural analogue whose pro-inflammatory activity is even greater than that of imiquimod. Unresponsiveness of some melanoma metastases to imiquimod in vivo corresponded to resistance towards imiquimod-induced apoptosis in vivo and in vitro. At the molecular level, the pro-apoptotic activity of imiquimod was independent of membrane-bound death receptors, but depended on Bcl-2 expression as demonstrated by overexpression of Bcl-2 in melanoma cells. Imiquimod is the first topical compound with the potential to bypass molecular mechanisms of apoptosis deficiency, a concept that may be relevant for other tumors as well.

Administration, Topical↗

PubMed2004

Targeting selectin functions in the therapy of psoriasis.

As leukocytes play a primary role in the immunopathogenesis of psoriasis, it is a reasonable assumption that preventing those cells from localizing to the sites of cutaneous inflammation can stop the disease process. Selectins, a family of three single-chain transmembrane adhesion molecules, which bind to carbohydrate moieties displayed on other cells, are pivotally involved in the initial steps of leukocyte recruitment, i.e. tethering and rolling along the endothelial lining of blood vessels. Thus, compounds impairing selectin functions have been developed to treat inflammatory disorders, such as psoriasis. Potential strategies to interfere with selectin functions include direct inhibition through monoclonal antibodies or small-molecule compounds, transcriptional regulation of selectin expression, and modulation of the post-transcriptional glycosylation of selectin ligands. More than a dozen different compounds targeting selectin functions are currently under development, several of which have shown promising effects on leukocyte recruitment and the therapy of inflammatory conditions under experimental conditions. However, based on preclinical and early clinical investigations, it appears that in some cases specifically targeting the function of single selectins may not be sufficient to effectively interrupt the inflammatory cascade. This is, at least in part, due to considerable redundancies and overlaps in the functions of the selectins, a notion that is corroborated by the apparently more pronounced therapeutic efficacy of some compounds with broader activity against several selectins. Overall, while targeting selectin functions promises rather selective and pathogenesis-based therapeutic approaches against psoriasis, the clinical value of such strategies, alone or in combination with other therapies, remains to be seen.

Drug Delivery Systems↗

PubMed2003

Tumor-selective induction of apoptosis and the small-molecule immune response modifier imiquimod.

BACKGROUND: The incidence of nonmelanoma skin cancer, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) is increasing, representing a major medical and economic problem. Imiquimod, a topical small-molecule immune response modifier, has shown efficacy toward BCC and actinic keratoses in clinical trials. Imiquimod acts both indirectly, via cytokine-mediated stimulation of cellular immune responses, and directly, through unknown mechanisms against tumor cells. We examined the mechanism by which imiquimod induces apoptosis in cancer cells. METHODS: Apoptosis was assessed by enzyme-linked immunosorbent assay, western blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays in five SCC cell lines, HaCaT cells (a spontaneously immortalized human keratinocyte cell line), and normal keratinocytes treated with imiquimod, with its analog resiquimod, or with neither. Expression of death receptors, caspases, and cytochrome c in the apoptotic signaling cascade was analyzed using western blot and flow cytometric analyses. The functional relevance of imiquimod-induced cytochrome c release was assessed by transfection of HaCaT cells with Bcl-2. Apoptosis in BCCs in vivo was assessed by TUNEL assays of imiquimod-treated and untreated tumors from three patients. Differences between treated and untreated cells and tumors were determined using a two-tailed Student's t test. RESULTS: Imiquimod, but not resiquimod, induced apoptosis in all SCC cell lines and HaCaT cells. This induction involved activation of several caspases and Bcl-2-dependent cytosolic translocation of cytochrome c but was independent of the membrane-bound death receptors Fas, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R1-R4 receptors, and tumor necrosis factor-R1 and -R2 receptors. Topical application of imiquimod to BCC tumors in vivo induced apoptosis. CONCLUSION: Imiquimod has the potential to induce apoptosis in skin cancer cells, possibly by circumventing mechanisms developed by malignant tumors to resist apoptotic signals.

Aminoquinolines↗

PubMed2003

[Scabies triggering Darier's disease].

An increased incidence of scabies has been noted in many countries. Difficulties may arise when unrecognized infestations trigger or aggravate other dermatological disorders. We present an instructive case of Darier's disease, which did not respond to appropriate therapy regimens due to constant triggering by an undetected underlying scabies infestation. In this case, a 44-year-old Italian man presented with typical symptoms of Darier's disease. In addition, the patient reported massive pruritus, which is rather uncommon in this disorder. The disease proved recalcitrant to established treatment regimens resulting in excessive treatment costs. We confirmed the diagnosis of Darier's disease by histopathological analysis, and, in addition, detected arthropod fragments in the upper epidermis. Systemic ivermectin and topical allethrin followed by acitretin and PUVA-bath therapy resulted in rapid improvement of the debilitating pruritus as well as alleviation of the symptoms of Darier's disease.

Administration, Topical↗