cortodoxone and Prostatic-Neoplasms

A dose of 125 mg of methylprednisolone was given iv each morning for 28 days to six patients with cancer. The posttreatment mean AM/PM serum cortisol (hydrocortisone) level of 19.55/11.27 microgram/dl showed a statistically significant (P less than 0.05) diurnal rhythm and did not differ from the pretreatment level (19.28/11.85 microgram/dl). The response to metyrapone (750 mg orally, every 4 hours X six doses) was assessed in five of the six patients before and after treatment. No abnormally low Compound S (11-deoxycortisol) levels were observed. The mean serum Compound S level (15.30 microgram/dl) achieved after treatment did not differ significantly from the pretreatment mean level (20.24 microgram/dl, P greater than 0.1). No adverse clinical effects were observed during or after this steroid treatment. Since significant hypothalamic-pituitary-adrenal suppression has not been demonstrated, this regimen appears to be safe for use in controlled studies of clinical efficacy.

Topics: Adenocarcinoma; Aged; Clinical Trials as Topic; Colonic Neoplasms; Cortodoxone; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Methylprednisolone; Metyrapone; Middle Aged; Prostatic Neoplasms

11α-Hydroxyprogesterone (11αOHP4) and 11β-hydroxyprogesterone (11βOHP4) have been reported to be inhibitors of 11β-hydroxysteroid dehydrogenase (11βHSD) type 2, together with 11β-hydroxytestosterone and 11β-hydroxyandrostenedione, and their C11-keto derivatives being inhibitors of 11βHSD1. Our in vitro assays in transiently transfected HEK293 cells, however, show that 11αOHP4 is a potent inhibitor of 11βHSD2 and while this steroid does not serve as a substrate for the enzyme, the aforementioned C11-oxy steroids are indeed substrates for both 11βHSD isozymes. 11βOHP4 is metabolised by 11βHSD2 yielding 11-ketoprogesterone with 11βHSD1 catalysing the reverse reaction, similar to the reduction of the other C11-oxy steroids. In the same model system, novel 11αOHP4 metabolites were detected in its conversion by steroid-5α-reductase (SRD5A) types 1 and 2 yielding 11α-hydroxydihydroprogesterone and its conversion by cytochrome P450 17A1 (CYP17A1) yielding the hydroxylase product, 11α,17α-dihydroxyprogesterone, and the 17,20 lyase product, 11α-hydroxyandrostenedione. We also detected both 11αOHP4 and 11βOHP4 in prostate cancer tissue- ∼23 and ∼32 ng/g respectively with 11KP4 levels >300 ng/g. In vitro assays in PC3 and LNCaP prostate cancer cell models, showed that the metabolism of 11αOHP4 and 11βOHP4 was comparable. In LNCaP cells expressing CYP17A1, 11αOHP4 and 11βOHP4 were metabolised with negligible substrate, 4%, remaining after 48 h, while the steroid substrate 11β,17α-dihydroxyprogesterone (21dF) was metabolised to C11-keto C

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Aged; Androstenedione; Cell Line, Tumor; Cortodoxone; HEK293 Cells; Humans; Hydroxyprogesterones; Male; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase

In vitro, ketoconazole has been shown to block testicular and adrenal 17,20-lyase, which converts progestins to androgens. At higher concentrations, it also inhibits 11 beta-hydroxylase, 20,22-desmolase and 17 alpha-hydroxylase. To determine the differential hormonal effects of a 2-week ketoconazole high-dose therapy, the plasma levels of 10 major androgens, gluco- and mineralocorticoids were measured in 14 previously untreated patients with metastatic prostate cancer. Within 24 h, plasma testosterone fell from 14.6 +/- 1.4 nmol/l (mean +/- SEM) to 3.7 +/- 0.7 nmol/l. Thereafter, it decreased to about 2.5 nmol/l and remained at that level. Plasma androstenedione and dehydroepiandrosterone decreased more gradually, respectively from 3.1 +/- 0.4 nmol/l to 0.64 +/- 0.17 nmol/l and from 6.6 +/- 1.0 nmol/l to 2.82 +/- 0.55 nmol/l (on day 14). In contrast, 17 alpha-hydroxyprogesterone and progesterone rose respectively 2- and 5-fold. Plasma cortisol and aldosterone levels remained unchanged whereas 11-deoxycorticosterone and 11-deoxycortisol rose by factors of 14 and 6.7 respectively. Plasma corticosterone also increased, but to a much lesser extent (3-fold). These results demonstrate that ketoconazole high dose therapy blocks mainly the 17,20-lyase of both adrenal and testis. In addition it inhibits mitochondrial 11 beta-hydroxylase to a lesser extent. The inhibition of 20,22-desmolase also seems to be of little clinical relevance. However, since clinical or laboratory symptoms suggestive of hypo-adrenalism have been reported in a small minority of patients, replacement therapy should be considered in such cases.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Cortex Hormones; Aged; Androgens; Androstenedione; Corticosterone; Cortodoxone; Dehydroepiandrosterone; Desoxycorticosterone; Humans; Hydroxyprogesterones; Ketoconazole; Male; Progesterone; Prostatic Neoplasms; Testosterone

A radioimmunoassay procedure for plasma 11-deoxycortisol (S) was developed using an antiserum prepared by immunizing rabbits with S-21-hemisuccinate bovine serum albumin and S-3-oxime-bovine serum albumin. Thereafter plasma S, cortisol (F) and adrenocorticotropic hormone (ACTH) responses to metyrapone were investigated in 13 normal adult males and 39 patients with prostatic cancer. The results were as follows: 1) The antiserum against S-3-oxime-bovine serum albumin had less cross reactivity (less than 10%) with other steroids than that against S-21-hemisuccinate bovine serum albumin and obtained a good standard curve. The intra-assay variance and interassay variance of this method using the former antiserum (N = 10) were 12.4% asd 14.9% respectively, and the blank value was 3.7 +/- 1.6 pg. 2) Basal levels of S. F and ACTH in plasma from 13 normal adult males, ranged 21 approximately 80 years, old, were 98.4 +/- 15.7 ng/dl (mean value +/- S.E.), 12.7 +/- 0.78 micrograms/dl and 30.6 +/- 3.02 pg/ml respectively. Those level increased to 7060 +/- 598 ng/dl, 24.3 +/- 1.69 micrograms/dl and 24.3 +/- 1.6 pg/ml at 9 a.m. following oral administration of metyrapone (30 mg/kg b.w.) at midnight. 3) Both basal levels and responses of plasma S and F to metyrapone increased remarkably, while those of ACTH were within the normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and AC normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and AC normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and ACTH responses to metyrapone were unchanged compared to normal adult males 2 approximately 4 weeks after discontinuation of the therapy, and this data suggested that estrogens had no inhibitory effect on the pitui

Topics: 17-Hydroxycorticosteroids; Adrenocorticotropic Hormone; Adult; Aged; Cortodoxone; Humans; Hydrocortisone; Male; Metyrapone; Middle Aged; Prostatic Neoplasms; Radioimmunoassay