Synergistic effects of pentoxifylline and dapsone in leucocytoclastic vasculitis.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
B M Czarnetzki
Publications and source records attributed to B M Czarnetzki.
Chemosensitivity testing of human malignant melanoma. A retrospective analysis of clinical response and in vitro drug sensitivity.
BACKGROUND: Clinical response rates in the treatment of patients with disseminated malignant melanoma are low and unpredictable. Several reports have documented that clonogenic assay systems for in vitro drug testing are capable of predicting resistance to therapy in vivo and might provide guidelines to improve clinical response rates. METHODS: Specimens from metastatic lesions of patients with malignant melanoma, predominantly from lymph nodes and skin, were disaggregated, exposed to a panel of 10 cytotoxic drugs for 1 hour, and subsequently cultured in agarose. Effects were calculated by the ability to form tumor colonies compared with an untreated control after 7-14 days. A retrospective comparison between the in vitro drug testing result and clinical response was possible in 19 cases. RESULTS: An average of 7.3 drugs per specimen were tested. A high degree of resistance was observed against all cytostatic agents studied independently of the tumor site. In 47 of 181 in vitro drug tests, tumor colony formation was reduced by 30-50%; in 17 of 181, the reduction was more than 50%. A retrospective analysis showed no clinical response in 11 cases and one mixed response in which patients received drugs that had been shown to be "resistant" in vitro. CONCLUSIONS: These results support the concept that in vitro drug testing promises to help avoid treatment with ineffective drugs and their associated toxic side effects. Furthermore, it may increase the likelihood of obtaining a clinical response in the treatment of disseminated malignant melanoma. The major limitation in the treatment of malignant melanoma is the lack of availability of effective agents for treatment.
Antineoplastic Agents↗
Mast cell involvement in murine hair growth.
We have examined the possibility that an involvement in hair growth regulation is one of the still obscure physiological roles of mast cells (MC) in normal skin. Using the murine hair cycle as a model, we first studied the number, localization and granulation status of skin MC during the hair cycle of C57 BL-6 mice. Shortly after the induction of hair growth (anagen) in the back skin of mice with resting (telogen) follicles, a sharp decline in the number of Giemsa-stainable MC was detected by morphometry. This was evident in depilation-induced, pharmacologically induced, and spontaneous anagen. By light and electron microscopy, the anagen-associated decline was correlated with the occurrence of substantial MC degranulation. In vivo, the IgE-independent MC secretagogues, compound 48/80 and ACTH, induced anagen in mouse telogen follicles after intracutaneous administration, while inhibitors of mast cell degranulation (cromoglycate, tiacrilast) and antagonists of selected MC products (clemastin, ranitidine, ketanserin) significantly retarded the induced development of anagen follicles in these mice. It is suggested that MC act via their secretory products as stimulators of anagen development in mice and that the murine hair cycle is an excellent model for studying growth regulatory functions of MC in developmentally regulated systems.
Animals↗
Stem cell factor, a novel cutaneous growth factor for mast cells and melanocytes.
Mechanisms affecting mast cell and melanocyte growth and function are still poorly understood. This report summarizes the current state of knowledge on a recently described growth factor for both these cell types and for primitive haematopoietic stem cells. Stem cell factor (SCF), also named mast cell growth factor or kit-ligand, has only recently been cloned and has been shown to be encoded on human chromosome 12. It may be of specific importance in cutaneous physiology and pathology since it is produced by several cell types in the skin (e.g. fibroblasts, keratinocytes, endothelial cells) and since it affects melanocyte and mast cell growth, survival, secretion and adhesion as well as migration into tissues. Defects in the genes encoding for the SCF receptor (c-kit-protein) have been shown to be responsible for human piebaldism. A pathogenetic role in mastocytosis has recently been proposed, but remains to be proven. SCF receptor expression is decreased on cells of some malignant cell lines compared to their physiological counterparts, making it unlikely that SCF is a key factor in malignant transformation and cellular hyperproliferation. In haematopoiesis, SCF acts primarily in concert with other growth factors, and we show here that alone in serum-free culture it has no effect on mast cell growth. Furthermore, there is evidence that besides SCF, additional mast cell growth factors are secreted by fibroblasts and keratinocytes, suggesting a complex orchestration of several growth factors in the regulation of cutaneous growth and differentiation in which SCF plays only one part.
Animals↗
Phenotypic evaluation of cultured human mast and basophilic cells and of normal human skin mast cells.
In order to evaluate various markers for human mast cells, two human mast/basophilic cell lines (HMC-1/KU812), cultured mast cells from the peripheral blood monocytic fraction and peripheral blood monocytes were compared with mast cells in tissue sections from normal skin, using histochemistry, enzyme histochemistry and immunohistochemistry. All reagents stained normal skin mast cells, with toluidine blue, tryptase reactivity and antibodies against the Fc epsilon RI and the stem cell factor receptor (c-kit) being most active. The cell lines and mast cells cultured from peripheral blood were negative for avidin, safranin and chymase, strongly positive for c-kit and variably reactive with all other reagents. All antibodies except AA1 against tryptase also stained one or several epidermal and dermal cell types or blood monocytes. Histochemical stains (toluidine blue, avidin) and reagents for the enzymes tryptase and chymase are thus specific markers for mast cells. The frequent reactivity of antibodies against mast cells with other cell types indicates interesting functional and ontogenetic relationships between these cells.
Antibodies, Monoclonal↗
Inhibitory effects of sulfonated shale oils (ammonium bituminosulphonates, Ichthyols) on enzymes of polyenoic fatty acid metabolism.
The two commercial pharmaceutical preparations of ammonium bituminosulphonates, Leukichthol and Dark Ichthyol, were shown to inhibit the formation of 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE) from external arachidonic acid by human polymorphonuclear leukocytes stimulated by ionophore A-23187 in a dose-dependent manner. Pure arachidonate 15-lipoxygenases from rabbit reticulocytes and soya beans, and the particulate prostaglandin endoperoxide synthase from sheep vesicular glands, were also inhibited. With the reticulocyte lipoxygenase, the Ichthyols suppressed the enzyme activity by two different mechanisms: (1) a prolongation of the lag period typical of lipoxygenase catalysis, and (2) by a lowering of the maximal enzymatic activity after the end of lag period. As expected, the first effect was reversed by the addition of the lipoxygenase product 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13-HpODE). Ammonium bituminosulphonates are thus universal inhibitors of lipoxygenase activities, and the latter are of potential importance in inflammatory dermatoses.
Arachidonic Acid↗
[Pilot study of the effect of interferon-alpha on atopic eczema].
In this pilot study 12 patients with moderate to severe atopic eczema were treated with 2 million IU interferon alpha 2a (Roferon A) three times weekly for 8 weeks and followed up for a further 10 weeks: 2 patients showed clear and 9 a slight to moderate reduction of their skin lesions; 1 patient got worse. Pruritus did not decrease and even increased in a few patients, and IgE levels showed no change during and after treatment. All patients noted mild, transient, flu-like symptoms. The efficacy of interferon alpha in the present therapeutic design for the treatment of atopic eczema must thus be classified as only moderate.
Adult↗
[Vitamin D3 and its analogs as multifunctional steroid hormones. Molecular and clinical aspects from the dermatologic viewpoint].
Since the identification of the cholesterol derivative 1,25-dihydroxy-vitamin D3 and its analogues as potent immunomodulatory, proliferation- and differentiation-regulatory molecules, the amount of data available on the effects of these agents on the skin and its appendages has grown exponentially. This review outlines recent progress in the understanding of the molecular biology and pathophysiology of vitamin D, and new strategies for the treatment of skin diseases are discussed. Focusing on psoriasis and preliminary clinical experiences, we discuss possible therapeutic targets and perspectives for these multifunctional steroid hormones in dermatology.
Animals↗
[Drug resistance of malignant melanoma. Mechanisms and possible modulation].
Response rates of metastatic malignant melanoma to cytostatic treatment are disappointingly low. Although immunomodulators such as interferons are more commonly being used in combination with cytostatics, no major breakthrough has been achieved. The mechanisms underlying the high chemoresistance of melanoma cells are so far ill-defined, and investigations are only just being initiated. Several mechanisms of chemoresistance have, however, been studied with other tumours and might be relevant for human melanoma: (1) "Classical" multidrug resistance, determined by the expression of the p-glycoprotein which resembles a membrane pump that eliminates natural and synthetic agents from the cell interior. Different drugs, including calcium antagonists, interfere with its function and can thus modulate chemoresistance. Preliminary data from investigations of these mechanisms indicate that p-glycoprotein is not, however, involved in the multidrug resistance of malignant melanoma. (2) Detoxification, involving glutathione-S-transferases (GST). GST are a multigene family of enzymes which inactivate alkylating agents by conjugation to glutathione. Their relevance for chemoresistance in melanoma has not yet been clarified. (3) Topoisomerase II, which is involved in DNA recombination and DNA transcription events and represents the target of several inhibitory cytotoxic agents. Low levels of the enzyme render cells resistant to the action of specific drugs. Again nothing is yet known regarding the relevance of this mechanism in human melanoma. Further studies of these potentially important resistance mechanisms are thus urgently needed in order to develop more effective therapies for advanced malignant melanoma.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[Biology of the hair follicle].
Explore the source record for details and available documents.
Alopecia↗
[Localized Sweet syndrome].
A 73-year-old women developed an inflammatory tumor on her right cheek within 3 weeks. The lesion measured more than 7 cm in diameter, contained a central crateriform depression and was studded with several sterile pustules. Histology showed a dense dermal infiltration of neutrophils, but no leukocytoclasia or destruction of dermal tissue. There was no associated leukocytosis or fever, but the patient suffered from recurrent chronic bronchitis. Because the acute inflammation was progressive under treatment with antibiotics, high-dose corticosteroids were given systemically. The tumor regressed quickly and resolved without scarring. Although this localized Sweet's syndrome is unusual, it fulfills several major and minor criteria of Sweet's syndrome and thus represents a rare form of this disease.
Aged↗
Correlation of proteolytic activities of organ cultured intact mouse skin with defined hair cycle stages.
The cyclic growth activity of the hair follicle is characterized by substantial remodelling of the extracellular matrix, yet, little is known about the proteolytic activities regulating this process. In murine skin, hair cycling is highly synchronized and is associated with dramatic remodeling of all skin compartments. We therefore have assessed, in this pilot study, proteolytic activities of murine skin from various stages of the depilation-induced hair cycle. We show that the defined proteolytic activities displayed by organ cultured intact mouse skin differ between hair cycle stages. Skin with all follicles in telogen or mid anagen displayed only minimal lysis of collagen type I gels, while early anagen skin had significant collagenase activity. Skin cultured on gelatin gels at the air-liquid interphase ('histoculture') completely lysed the gel within 5 days when all follicles were in early anagen, while this was not observed with mid and very late-anagen skin. Zymography of conditioned medium from these cultures revealed the secretion of activated interstitial collagenase and of gelatinases of 72 and 92 kDa, with the maximum of interstitial collagenase activity secreted by anagen IV skin. Addition of TPA or TNF-alpha to the culture medium stimulated secreted collagenase type I activity. The C 57 BL-6 mouse offers an attractive model for dissecting and manipulating hair cycle-associated proteolysis in a physiologically relevant system.
Animals↗
Interferon treatment of patients with chronic urticaria and mastocytosis.
Explore the source record for details and available documents.
Adult↗
Combination of etretinate with cyclosporine in the treatment of severe recalcitrant psoriasis.
Explore the source record for details and available documents.
Aged↗
Prevalence of cholinergic urticaria in young adults.
BACKGROUND: Cholinergic urticaria is primarily seen in young adults, but little is known about its prevalence. OBJECTIVE: A prospective study was designed to investigate the frequency and severity of cholinergic urticaria in this age group. METHODS: Four hundred ninety-three high school and university students (15 to 35 years of age) were examined for cholinergic urticaria by means of a questionnaire and partly by exercise provocation tests. RESULTS: The overall prevalence of cholinergic whealing was 11.2%, with most of the affected persons being older than 20 years. The highest prevalence was observed in the age group of 26 to 28 years (20%). Apart from a small group of severely afflicted persons with systemic symptoms (11%), reactions were mostly mild and restricted to fleeting, pinpoint-size wheals (76%). Eighty percent of affected subjects were not troubled by their condition, and only 22% had ever sought medical attention. CONCLUSION: The study shows a high prevalence of cholinergic urticaria, but the condition is mostly mild.
Adolescent↗
Lysis of allogeneic and autologous melanoma cells by IL-7-induced lymphokine-activated killer cells.
In order to assess the potential of interleukin 7 (IL-7) as an immunotherapeutic agent in human melanoma, we have evaluated the in vitro activity of IL-7-induced lymphokine-activated killer (LAK) cells from patients with advanced melanoma against allogeneic and autologous melanoma cells. Peripheral blood lymphocytes (PBLs) from 14 patients with stage III melanoma were isolated and incubated in the presence of 1,000 U ml-1 IL-7 and 100 U ml-1 IL-2 for comparison. LAK-cell activity was determined by a 24 h cytotoxicity assay using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. The activity of IL-7-induced LAK cells against two allogeneic melanoma cell lines was 32.7% (+/- 17.9) against SK-Mel-37 and 38.1% (+/- 12.5) against SK-Mel-23 at an effector-to-target (E/T) ratio of 20:1. The activity of IL-2-induced LAK cells was significantly higher against SK-Mel-37 (78 +/- 24.6%) and against SK-Mel-23 (73.5 +/- 19.7%). IL-7 and suboptimal doses of IL-2 (10 U ml-1) were found to have a co-stimulatory on lymphocyte proliferation as well as on LAK activity. Against autologous melanoma cells, the activity of IL-7- and IL-2-induced LAK cells did not differ significantly (55.8 +/- 25.6% versus 68.7 +/- 21.7% respectively). In two patients, IL-7-induced LAK-cell activity against autologous melanoma cells exceeded even that of IL-2 significantly (67% vs 35% and 95% vs 82%). Levels of tumour necrosis factor alpha (TNF-alpha) in the supernatants of LAK-cell cultures generated by IL-7 were lower than those of IL-2-generated LAK-cell cultures. These results suggest that IL-7 is a potential alternative to immunotherapy with IL-2 in terms of efficacy and possible side-effects and encourages pilot studies with IL-7 in melanoma patients.
Adult↗
Bulge-activation hypothesis (continued)
Explore the source record for details and available documents.
Apoptosis↗
In vitro sensitivity of human melanoma cells to chemotherapeutic agents and interferons.
The purpose of our study was to evaluate systematically the anti-proliferative effects of eight chemotherapeutic drugs as well as of four recombinant interferons (IFNs) (alpha-2a, alpha-2b, beta, gamma). All drugs and IFNs were tested separately and in combination at several concentrations on four human melanoma cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5,-diphenyltetrazolium (MTT) test. In all cases, drug inhibitory concentrations of chemotherapeutic agents required to kill 25% of melanoma cells (IC25) in vitro were in the range of the maximal achievable plasma peak level in vivo. Sensitivity to the anti-proliferative action of bleomycin, DTIC, doxorubicin, cisplatin and carboplatin was similar for all melanoma cell lines, whereas cell lines exposed to 5-fluorouracil (5-FU), vindesine and fotemustine differed up to 26-fold in their sensitivity. Studies with IFN showed that IFN-beta and IFN-gamma proved to be more antiproliferative than IFN-alpha in a dose-dependent fashion in all cell lines. However, the ability of IFNs to improve cytotoxicity of chemotherapeutic agents was limited. Pre-incubation of melanoma cells with IFN as well as exposure to IFN after incubation with the drugs showed mainly additive effects (231/256). These results confirm the high chemoresistance of human melanoma cells, independently of the drug chosen. Combinations of chemotherapeutic agents with IFN will provide additional therapeutic benefit, but are unlikely to change the overall high chemoresistance of human melanoma cells.
Antineoplastic Agents↗