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S Hirschel-Scholz

Publications and source records attributed to S Hirschel-Scholz.

17 recordsLinked to original sources
PubMed1992

Cancer metastasis--a multistep process.

Dermatologists are confronted daily with proliferative growths which can reach considerable size, but mean no danger to the patient. Seborrheic keratoses are one example. Other growths, such as basal cell carcinoma, are locally destructive. Normally, however, we do not hesitate to reassure the patient about the benignity of the tumor once excised. The malignancy of squamous cell carcinomas and melanoma, however, is undoubted. Thus, excessive proliferation and even local invasiveness are not sufficient to define malignancy. It is the life-threatening aspect of metastasis that physicians are mostly concerned about.

Animals↗
PubMed1991

Anetodermic prurigo nodularis (with Pautrier's neuroma) responsive to arotinoid acid.

A woman had symmetrically distributed pruritic nodules for more than 40 years. Microscopically they were characterized by proliferation of nonmyelinated nerve fibers (Pautrier's neuroma) and a total absence of epidermal involvement. Anetoderma developed at the site of former nodules. Her condition responded favorably to repeated retinoid therapy with regression of nodules in those sites in which retinoid dermatitis had developed.

Aged↗
PubMed1991

Differential protease expression by cutaneous squamous and basal cell carcinomas.

To assess the postulated role of plasminogen activation in tumor invasion, we have investigated the cellular sites of synthesis for urokinase-type (uPA) and tissue-type (tPA) plasminogen activators and their inhibitors (PAI-1 and PAI-2) in two human cutaneous neoplasia that differ in their metastatic potential. The combined use of zymography on tissue sections and in situ hybridization demonstrates that uPA is produced by malignant cells of squamous cell carcinomas (SCC) but not by basal cell carcinomas (BCC), whereas tPA is detected exclusively in nonmalignant dermal tissue. In addition, we show that SCC neoplastic cells simultaneously produce variable amounts of PAI-1, and that PAI-1 production correlates inversely with uPA enzymatic activity. These observations establish that invasive human malignant cells in vivo can activate plasminogen through uPA production during the early phases of tumor growth; they also demonstrate that the proteolytic activity of tumor cells can be modulated by the concomitant production of PAI-1. Because SCC have a higher invasive and metastatic potential than BCC, our findings lend further support to the involvement of plasminogen activation in malignant behavior.

Basal Cell Carcinoma↗
PubMed1989

Isotretinoin differs from other synthetic retinoids in its modulation of human cellular retinoic acid binding protein (CRABP).

Isotretinoin differs from acitretin and Ro137410 by its striking sebostatic effect in acne after oral, but not topical, administration. The reason for this is not yet understood. Previous studies indicate that cellular retinoic acid binding protein (CRABP) might be implicated in the action of synthetic retinoids. We, therefore, compared the three retinoids for their ability to increase epidermal CRABP levels after systemic and topical treatment. Oral treatment with acitretin and Ro137410 led to a striking increase of epidermal CRABP (from 2.6 +/- 0.9 to 16.2 +/- 2.9, P less than 0.004 and from 2.5 +/- 1.2 to 21.5 +/- 3.4 pmol/mg protein, P less than 0.004, respectively), while isotretinoin failed to induce a comparable rise (3.2 +/- 1.6 before and 3.7 +/- 0.7 pmol/mg protein after treatment), although it displayed in all patients a striking sebostatic effect. After topical application, the increase of CRABP was comparable for all three compounds. The interaction of isotretinoin with the epidermis seems to be different from other synthetic retinoids only after systemic treatment, a finding that parallels clinical observations.

Acitretin↗
PubMed1989

Ligand-specific and non-specific in vivo modulation of human epidermal cellular retinoic acid binding protein (CRABP).

Retinoic acid (RA) is bound intracellularly by a specific, low molecular weight protein (CRABP), that is unrelated to its nuclear receptor and whose function and regulation are still unknown. In the present study we were able to obtain an in vivo modulation of CRABP by different stimuli in one of the major target organs of RA: the human skin. We found increased CRABP after daily application during 4 days of natural or synthetic retinoids (RA, acitretin, isotretinoin, Ro137410, retinol), that have either a high affinity to CRABP or can be transformed into RA. Only Ro150778 with no affinity and no reported transformation had no effect. No macro- or microscopical changes could be observed with any of the tested compounds. Induction of inflammatory and hyperproliferative changes in the skin by topical dithranol treatment, UVB irradiation or scotch tape stripping also induced a significant increase of CRABP 3 days after exposure. Topical diflucortolone showed not only a tendancy to decrease intrinsic CRABP levels, but significantly reduced the retinoid stimulated rise of CRABP. Thus we conclude that the increase of CRABP in a fully differentiated adult tissue seems to be a biological phenomenon following processes of inflammation and proliferation with a lag of several days, while retinoids seem to be able to induce such a rise independently of, or before, the appearance of such processes. Corticosteroids seem to be inhibitors of this reaction. We discuss the hypothesis that CRABP might function as an intracellular 'buffer' in the case of RA overload.

Acitretin↗
PubMed1988

Protection from progressive renal failure and hyperparathyroid bone remodeling by WR-2721.

In chronic renal failure (CRF), secondary hyperparathyroidism (sHPT) plays a major role in skeletal lesions and also probably in the deterioration of renal functions consecutive to nephrocalcinosis. In this study we tested whether WR-2721 [S-,2-(3-aminopropylamino)-ethylphosphorothioic acid], an inhibitor of parathyroid hormone (PTH) secretion, could prevent the deleterious effects of sHPT at both the bone and kidney level in an animal model of CRF. Rats were either subtotally nephrectomized (NX) or sham-operated (SHAM). They were then pairfed a high phosphorus (1.4%), middle Ca (0.6%) diet. This regimen accelerated the deterioration of renal function in NX rats which displayed signs of severe sHPT in bone (three- to fourfold increase in osteoclast number and resorption surfaces) and kidney (sixfold increase in Ca content) after four weeks. Chronic administration of WR-2721 (20 mg = 0.093 mmol/kg s.c. twice daily) during four weeks completely prevented the progressive elevation of both plasma urea and inorganic phosphate, and the fall of plasma Ca. It also prevented kidney Ca accumulation to the same extent as parathyroidectomy. However, WR-2721 given at this dose only partially prevented the histomorphometric indices of increased bone resorption and formation. This discrepant response suggests that WR-2721 could exert an additional protective effect at the kidney level that might be related to its property of acting as a free radical scavenger. In conclusion, this study suggests that WR-2721 might be a useful compound in CRF, not only because it inhibits PTH secretion, but also because it could protect against the deleterious effect of secondary hyperparathyroidism on kidney functions.

Amifostine↗
PubMed1988

Arotinoid acid (Ro 13-7410): a pilot study in dermatology.

Ro 13-7410 was given to 29 patients (a total of 38 treatment courses) for 7.5 weeks (range 4-23). This compound is one of the most potent retinoids ever synthetized and has the highest affinity to human skin cellular retinoic-acid-binding protein. At therapeutically active doses, it did not induce the commonly seen mucocutaneous signs of retinoid toxicity such as scaling and cheilitis; over 0.5 microgram/kg body weight/day, it very frequently induced an eczematous retinoid dermatitis. This pilot study provides some indications on what appears to be in several aspects a drug quite distinct from retinoids previously used in humans.

Adult↗
PubMed1988

Interference of WR-2721 with magnesium metabolism: mechanism of action.

Recently, a radio-, and chemoprotective drug, WR-2721 (S-2-[3-aminopropylamino]-,ethylphosphorothioic acid) proved to be a potent inhibitor of parathyroid hormone (PTH) secretion. In human subjects, it not only decreased plasma Ca, but also induced a significant fall in the plasma magnesium level. In the present study in rats we investigated the mechanism(s) of this hypomagnesemic effect. In intact rats WR-2721 (0.7 mmol/kg s.c.) decreased plasma Mg from 0.96 +/- 0.03 to 0.67 +/- 0.02 mmol/l (p less than 0.001) within 2 h. In thyroparathyroidectomized (TPTX) animals plasma Mg fell from 0.93 +/- 0.03 to 0.72 +/- 0.03 mmol/l (p less than 0.001) 2 h after the same dose of WR-2721. In both intact and TPTX animals renal clearance experiments revealed that the WR-2721-induced hypomagnesemia was associated with an increase in urinary Mg excretion. This renal effect was not accompanied by a significant elevation in urinary sodium excretion, contrasting strikingly with the magnesuric action of furosemide. In bilaterally nephrectomized rats the hypomagnesemic effect of WR-2721 was abolished. Finally, the intracellular and/or tissue Mg contents of circulating lymphocytes, red blood cells, skeletal muscle, liver, bone and salivary glands were not significantly influenced by hypomagnesemic doses of WR-2721. In conclusion, these results indicate that the effects of WR-2721 on Mg metabolism cannot be ascribed to alterations in PTH and calcitonin secretion. Furthermore, they strongly suggest that the WR-2721-induced hypomagnesemia is mainly due to an inhibition of tubular Mg reabsorption.

Amifostine↗
PubMed1987

Prevention of parathyroid hormone-dependent nephrocalcinosis by chronic administration of the organic phosphorothioate WR-2721.

Pharmacological inhibition of parathyroid hormone (PTH) secretion has been the object of several experimental and clinical trials in the past. It is only recently that a drug, WR-2721 [S-,2-(3-aminopropylamino)-,ethylphosphorothioic acid], has been shown to effectively inhibit PTH secretion in euparathyroid subjects and in parathyroid cancer patients within a few hours after its administration. In the present study we tested its long term efficacy as a PTH inhibitor in a model of nephrocalcinosis resulting from secondary hyperparathyroidism. Intact and thyroparathyroidectomized (TPTX) rats were pair-fed on a low Ca (0.2%)-high phosphorus (1.6%) diet (nephrocalcinotic diet) or on a normal Ca (1.1%)-normal phosphorus (0.8%) diet for 7 days. Simultaneously, either 0.2 mmol/kg of WR-2721 or its solvent was injected subcutaneously twice daily. The intact animals on the nephrocalcinotic diet had an increased urinary cyclic AMP excretion and important renal Ca accumulation. This nephrocalcinosis was markedly reduced by WR-2721 treatment. The kidney Ca content of the WR-2721-treated rats was 58 +/- 6% lower than that of the nontreated animals. The low Ca-high phosphorus diet did not cause nephrocalcinosis in the TPTX rats. WR-2721 failed to reduce the nephrocalcinosis induced by 1,25 dihydroxyvitamin D3 intoxication in TPTX rats fed the normal Ca-normal phosphorus diet. In conclusion, the present study suggests that chronic treatment with WR-2721, a potent inhibitor of PTH secretion, may be effective for preventing the deleterious consequences of hyperparathyroidism, such as nephrocalcinosis.

Amifostine↗
PubMed1987

Human skin retinoid-binding proteins and therapy with synthetic retinoids: a still unexplained link.

Human skin contains several proteins that could bind retinoids. One is the retinol-binding protein (RBP, the plasma carrier of natural vitamin A, retinol, which was found to also bind retinoic acid (RA) in vitro. A polyacrylamide gel electrophoresis technique followed by protein immunoblot analysis with an antiserum specific against RBP was developed. This technique allowed us to study the binding of several natural and synthetic retinoids to the plasma RBP; it was found that only natural retinoids bind to RBP in vitro; RA binding was found to induce major conformational changes in the protein. The technique was then used for the study of RBP in human epidermal and dermal extracts; this showed that RBP degradation with loss of binding properties for retinol occurred within the epidermis. A polyacrylamide gel electrophoresis binding assay was developed for studying cellular retinol-(CRABP) and retinoic acid-(CRABP) binding protein in human skin cytosolic extracts. CRABP was (1) found at much higher levels in normal epidermis than in the dermis (2); dramatically elevated in psoriatic plaques and in some retinoid-responsive dermatoses, and (3) up-modulated by both topical and systemic administration of natural and synthetic retinoids. Such alterations were not observed for CRBP. From these and other observations presented here, it appears that CRABP should be one of the first candidates to be carefully analyzed in the search of the cellular receptor for the mediation of the synthetic retinoids pharmacological effects.

Benzoates↗
PubMed1987

Management of hypercalcemia in relation to pathophysiology.

Hypercalcemia results from an imbalance between the fluxes of calcium (Ca) entering and leaving the extracellular space. The two most important influxes are the net intestinal Ca absorption and the net skeletal Ca resorption, whereas the renal excretion represents the main route of elimination. When produced in excess, various factors, particularly calciotropic hormones and cytokines, can disturb the Ca fluxes at intestinal, skeletal and renal tubular sites. If the excessive production of these substances cannot be controlled by surgical or pharmacological means, the next most rational therapeutic strategy should be aimed at correcting those Ca fluxes which are abnormally increased. In hypercalcemia of malignancy (HM), an augmentation in net bone resorption (BR) is observed in most patients. However, a sustained stimulation in tubular Ca reabsorption (TRCa), despite correction of volume depletion by saline infusions, may not only contribute to the hypercalcemia, but in some cases it appears to be the prevailing disturbance. In these patients the effects of the antiresorbing agent clodronate (500 mg/8 h iv in one single infusion) is incomplete, despite the normalisation of BR. Thus, administration of an antiresorbing agent, such as clodronate, is the treatment of choice in HM with elevated BR and normal TRCa. It should be given with other therapeutic agents when a sustained increase in TRCa is the prevailing mechanism for hypercalcemia. In this regard, experimental studies suggest that the agent WR-2721, which specifically inhibits TRCa could be an effective drug for rapidly lowering plasma Ca in HM with high TRCa.

Amifostine↗
PubMed1986

Normalization of hypercalcemia associated with a decrease in renal calcium reabsorption in Leydig cell tumor-bearing rats treated with WR-2721.

The Rice-500 Leydig cell tumor (LCT) in Fischer rats is a model of humoral hypercalcemia of malignancy (HHM). In this model, the elevation of plasma calcium (Ca) does not result merely from an increased bone resorption, but also from an enhanced tubular Ca reabsorption (TRCa). We investigated the hypocalcemic response to WR-2721 [S-2,2-(3-aminopropylamino)-, ethylphosphorothioic acid] in LCT-bearing Fischer rats. WR-2721 is a potent inhibitor of normal and aberrant parathyroid hormone (PTH) secretion. Moreover, it exerts a PTH-independent inhibitory effect on TRCa. In hypercalcemic LCT-bearing rats WR-2721 induced a fall in plasma Ca from 3.24 +/- 0.12 to 2.66 +/- 0.23 mmol/liter within 2 h after one single injection of 0.7 mmol/kg body wt. The decrement in plasma Ca was associated with a marked increase in urinary Ca excretion, indicating an inhibition of TRCa. The elevated urine cyclic AMP of LCT-bearing rats, however, was not altered by WR-2721 treatment. These results suggest that in this HHM model, WR-2721 can normalize calcemia through its PTH-independent inhibitory effect on TRCa. WR-2721 could therefore be an effective drug to treat human hypercalcemia of malignancy, particularly in those tumors wherein a markedly enhanced renal Ca reabsorption contributes to the elevation of the plasma Ca level.

Absorption↗
PubMed1985

Suppression of parathyroid secretion after administration of WR-2721 in a patient with parathyroid carcinoma.

WR-2721 is an organic thiophosphate, known as a radioprotective agent, which also inhibits parathyroid hormone (PTH) secretion and reduces the plasma calcium level in euparathyroid animals and human subjects. In this study we present evidence that WR-2721 is also able to reduce an abnormal PTH secretion in a case of parathyroid carcinoma. The intravenous infusion of a single dose (750 mg/m2) of WR-2721 was followed within 3 h by a reduction in the plasma concentration of PTH by 60%, and of Ca by about 0.45 mmol/l. These changes were associated with a diminution in urinary cAMP excretion. Based on this observation it appears that WR-2721 merits further investigation as a possible agent for the medical treatment of hyperparathyroidism.

Amifostine↗
PubMed1985

Inhibition of parathyroid hormone secretion and parathyroid hormone-independent diminution of tubular calcium reabsorption by WR-2721, a unique hypocalcemic agent.

Hypocalcemia has been observed in patients receiving WR-2721 [S-,2-(3-aminopropylamino)-, ethylphosphorothioic acid]. WR-2721 is a compound that, after being dephosphorylated, provides protection of normal tissues against radio- and chemotherapy. The hypocalcemic response was accompanied by a decrease in the plasma level of parathyroid hormone (PTH) and by hypomagnesemia. Our present studies in rats on the mechanism of the hypocalcemic effect of WR-2721 indicate that: (a) The phosphorylated and dephosphorylated form of WR-2721 induced an equal dose-dependent decrement in plasma calcium. (b) In intact rats a maximal hypocalcemic dose of WR-2721 reduced urinary cyclic AMP excretion from 70.5 +/- 6.3 to 38.2 +/- 3.1 pmol/ml glomerular filtration rate (GFR), a level comparable to that observed (35.9 +/- 5.2 pmol/ml GFR) in thyroparathyroidectomized (TPTX) rats. (c) WR-2721 given to TPTX rats did not significantly interfere with the calcemic effect of bovine PTH 1-34 infused at 2.5 IU/h. Likewise, the drug did not impair the PTH actions on the renal Ca and inorganic phosphate (Pi) handling, and on the urine cyclic AMP excretion. (d) In TPTX rats made normocalcemic by low Pi diet, the hypocalcemic effect of WR-2721 was only about 25% of that observed in intact animals. However, it was associated with increased urine Ca per milliliter GFR, indicating a PTH-independent inhibitory effect on tubular Ca reabsorption. (e) In WR-2721-treated intact rats, prevention of hypomagnesemia by infusing magnesium chloride did not reduce hypocalcemia. In conclusion, the hypocalcemic effect of WR-2721 is not dependent upon the presence of a phosphate group in the molecule and is not causally related to hypomagnesemia. WR-2721 appears to be a unique hypocalcemic pharmacologic agent with strong inhibitory activity on PTH secretion and additional PTH-independent action on renal Ca reabsorption.

Amifostine↗