Biomedical subjects

C J van Uffelen

Publications and source records attributed to C J van Uffelen.

5 recordsLinked to original sources

PubMed1997

Antiprogestins and iatrogenic glucocorticoid resistance.

The antiglucocorticoid action of the antiprogestin RU 38486 has interfered with its successful clinical application in long-term treatment. Several new antiprogestins (Org 31710, Org 31806 and ZK 98299) have recently been developed with the aim to eliminate this side-effect. We have used a human lymphocyte proliferation assay to estimate the antiglucocorticoid potency of RU 38486 and the newer antiprogestins. In this assay 100 nmol/L RU 38486 shifted the dexamethasone inhibition curve by at least one order of magnitude. The other antiprogestins showed no effect at 100 nmol/L. RU 38486 (30 nmol/L) was able to antagonize 1000 nmol/L dexamethasone. The other antiprogestins showed only slight effects even at 1000 nmol/L. We conclude that the new antiprogestins have antiglucocorticoid effects that are one to two orders of magnitude lower than that of RU 38486. This may make them more suitable than RU 38486 for application in long-term antiprogestin treatment.

Binding, Competitive↗

PubMed1996

Somatostatin receptor manipulation.

The expression of somatostatin receptors (ssts) on human tumours is the basis for the successful therapeutic and diagnostic application of (radiolabelled) somatostatin analogues. Manipulation (up-regulation) of sst expression might improve the uptake of radioligand in in vivo scintigraphy of human sst-positive tumours, as well as the potential success of radiotherapy using radiolabelled SRIF analogues. In colonal pituitary cell lines, agonist exposure (SRIF-14, SRIF-28, octreotide) has been shown to either reduce or increase sst (subtype) expression, suggesting cell-type-specific responsiveness. In addition, glucocorticoids and oestrogens were shown to down- and up-regulate, respectively, sst numbers. So far, little information is available with respect to sst (subtype) regulation in non-pituitary-derived cell types. We have found that sst expression in the model of the transplantable prolactin (PRL)-secreting rat pituitary tumour 7315b is mainly dependent upon the presence of oestradiol (E2), both in vivo and in vitro. This tumour is sst negative in vivo. In vitro, the addition of E2 induces sst expression (sst2 and sst3 subtypes). The in vivo administration of E2 (20 micrograms/day subcutaneously) to 7315b-tumour-bearing rats induces sst2 mRNA expression. The absence of sst expression in 7315b tumours in vivo may be due to the inhibition of ovarian E2 production by the high circulating PRL levels in the 7315b-prolactinoma-bearing rats. Indeed, no detectable E2 levels were found in the serum of 7315b-tumour-bearing rats. Taken together, our data suggest that the 7315b rat prolactinoma can indirectly manipulate (down-regulate) its own sst expression, in vivo, via its host. This experimental 7315b prolactinoma model might be representative for most untreated female prolactinoma patients. Clinically, patients with microprolactinomas do not benefit from octreotide treatment.

Animals↗

PubMed1995

Temperature-induced down-regulation of the glucocorticoid receptor in peripheral blood mononuclear leucocyte in patients with sepsis or septic shock.

OBJECTIVE: Activation of the hypothalamic-pituitary-adrenal axis is of vital importance during critical illness. We have studied the adaptive mechanisms which occur at the level of the glucocorticoid receptor in glucocorticoid target tissues in patients with sepsis or septic shock. DESIGN: The effects of hypercortisolaemia, hyperthermia and cellular composition on number of glucocorticoid receptors per cell and their affinity were evaluated, both in vitro and in vivo, in peripheral blood mononuclear leucocytes of control subjects and in patients with sepsis or septic shock. SUBJECTS: Fifteen patients (age 25-79) with sepsis or septic shock who were admitted to an intensive care unit were studied. The control group consisted of 24 healthy laboratory employees. MEASUREMENTS: The binding capacity and affinity of the glucocorticoid receptors were measured and compared to clinical data and the plasma cortisol concentrations. RESULTS: Hypercortisolaemia, in vitro, resulted in a decreased affinity and a decreased binding capacity of the glucocorticoid receptor. In vitro, hyperthermia as well as variations in the cellular composition did not influence the glucocorticoid receptor. In vivo, there was no change in the number of receptors per cell in patients with sepsis or septic shock as compared to healthy controls. However, a decreased affinity of the glucocorticoid receptor was observed. There was a weak but significant negative correlation between body temperature and the number of glucocorticoid receptors in the patient group. There was no relation between circulating cortisol concentrations and glucocorticoid receptor affinity and number. CONCLUSIONS: There is no obvious regulation of the number of glucocorticoid receptors by plasma cortisol concentrations in vivo. The decreased affinity of the glucocorticoid receptor together with the negative correlation between hyperthermia and the number of glucocorticoid receptors in patients with sepsis or septic shock suggest that hypothalamic-pituitary-adrenal axis activation during critical illness is accompanied by peripheral adaptation in glucocorticoid receptor number and affinity.

Adult↗

PubMed1993

Effect of culture conditions on androgen sensitivity of the human prostatic cancer cell line LNCaP.

Several effects of androgens on LNCaP-FGC prostate tumor cells showed a biphasic pattern. Stimulation of growth and inhibition of secretion of prostatic acid phosphatase (PAP) was observed at low androgen concentrations (below 1 nM of the synthetic androgen R1881), and inhibition of growth and stimulation of PAP secretion was observed at higher concentrations. In contrast, prostate specific antigen (PSA) secretion did not show this biphasic response pattern. Comparable effects were found for two sublines of the LNCaP-FGC cells: an early (passage 20, androgen-dependent) and relatively late (passage 70, androgen-sensitive) passage of the cells. Culturing of both sublines in the presence of a high concentration of androgens (10 nM R1881) resulted initially in a decrease in growth rate, but the cells started to proliferate within 3 weeks. These cells became less sensitive to androgens, lost their biphasic response pattern, and showed reduced androgen receptor levels. Three weeks after removal of the excess of androgens, the passage 70 cells regained a biphasic growth response to androgens. Culture in medium without steroids but with EGF resulted in a decrease of both androgen sensitivity and androgen receptor level. In conclusion, rapid changes of the androgen sensitivity and receptor level of the LNCaP cells occurred under the influence of culture conditions. These changes were partly reversible and, therefore, were most likely due to adaptation of the cells.

Acid Phosphatase↗

PubMed1991

The human prostatic cancer cell line LNCaP and its derived sublines: an in vitro model for the study of androgen sensitivity.

The LNCaP-FGC (fast growing colony) cell line, a subline derived from the LNCaP cell line, shares all the main characteristics, including its androgen sensitivity, described for the parental line. A number of sublines originating from the FGC line were characterized with respect to their response to steroid-depleted medium and to the synthetic androgen R1881. The growth of FGC cells in DCC medium with 0.1 nM R1881 was stimulated 2-3-fold compared to growth in DCC medium only. FGC cells that were continuously grown in DCC medium did not die, but their growth rate was clearly slowed down, and the cells remained responsive to androgen. These cells, therefore, have the androgen-sensitive, rather than the androgen-dependent phenotype. As cells of the subline FGC-JB could not be maintained in DCC medium, these cells better represent the androgen-dependent cell type. In contrast to the FGC line, cells of the R line, grew equally well in medium with complete or DCC serum. Under none of these culture conditions, R cells could significantly be stimulated further with R1881. Further analysis of the LNCaP-FGC sublines should provide valuable information concerning the development of androgen resistance in human prostate cancer.

Androgens↗