Merkel cell carcinoma was first described in 1972 by Toker and is an aggressive neuroendocrine skin tumor with a high metastatic potential. Merkel cell carcinoma is thought to derive from the neuroendocrine (Merkel) cells of the skin, although in contrast to fetal and especially adult Merkel cells, Merkel cell carcinomas express high levels of the Bcl-2 oncoprotein. Bcl-2 is capable of blocking programmed cell death and has been shown to play an important role in normal cell turnover, tumor biology, and chemoresistance. High Bcl-2 expression leading to prolonged survival of cells may therefore be of importance in the biological and clinical characteristics of Merkel cell carcinoma. In a SCID mouse xenotransplantation model for human Merkel cell carcinoma, we investigated the influence of the bcl-2 antisense oligonucleotide G3139 (Genta) on tumor growth in comparison with control oligonucleotides or cisplatin. Bcl-2 antisense treatment, targeting the first six codons of the bcl-2 mRNA, resulted in either a dramatic reduction of tumor growth or complete remission, whereas reverse sequence and two-base mismatch control oligonucleotides or cisplatin had no significant antitumor effects compared with saline-treated controls. Apoptosis was enhanced 2.4-fold in the bcl-2 antisense treated tumors compared with the saline-treated group, and no other treatment showed a comparable increase in apoptosis. Our findings suggest that bcl-2 antisense treatment may be a novel approach to improve treatment outcome of human Merkel cell carcinoma.
Treatment with 8-methoxypsoralen plus ultraviolet A radiation and extracorporeal photochemotherapy (photopheresis) are widely used for the treatment of psoriasis and other inflammatory skin diseases, graft-versus-host disease, and mycosis fungoides. As the ratio of Th1 and Th2 cells appears to be critical for pathogenesis and progression of these disorders the effect of psoralen plus ultraviolet A on Th1 and Th2 cytokine production by CD4+ lymphocytes was investigated. Human peripheral blood lymphocytes were incubated in the presence of anti-CD3, rh-IL2, and rh-IL4 for 48 h. After subsequent stimulation with rh-IL2 and rh-IL4 for 72 h cells were treated with 8-methoxypsoralen (100, 500, 1000 ng per ml) plus ultraviolet A (2 J per cm2) and incubated for a further period of 5 h in the presence of ionomycine, phorbol-12-myristate acetate and monensin. Fluorescence-activated cell sorter analysis revealed a significant reduction of interleukin-2- and interferon-gamma-producing CD4+ cells upon psoralen plus ultraviolet A treatment depending on the concentration of 8-methoxypsoralen. In contrast, interleukin-4-producing CD4+ cells were increased, indicating a shift from Th1 to a Th2 cell cytokine profile upon psoralen plus ultraviolet A treatment. These results indicate that 8-methoxypsoralen photochemotherapy of lymphocytes is able to modulate their Th1/Th2 distribution. Inhibition of Th1 cytokine expression by psoralen plus ultraviolet A might help to explain its beneficial effects in the treatment of Th1 dominated skin diseases.
These results provide morphological evidence that in normal human skin hsp27 might act as a chaperone of cornification. Investigations of the molecular hsp27 interactions with the proteins of the cornified cell envelope are necessary to gain further insight into terminal keratinocyte differentiation and disorders of keratinization.
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