mepitiostane and epitiostanol

Additive endocrine therapy of breast cancer was first initiated by androgen treatment through intramuscular administration which proved to be effective in about 25% of trial cases. It was followed by another trial of massive administration of estrogens mainly to patients of more than 60 years of age, and this showed a similar efficacy. Under these circumstances, additive endocrine therapy's position was established as a special therapy for advanced breast cancer. Breast cancer patients have a considerably longer period of progress after disease recurrence than in other types of cancer, so oral androgens were developed for treating recurrent breast cancer patients at home. However, the side effects of androgens (e.g., virilization, hepatic disorders) presented problems with Long-term administration. Since then more androgens with less side effects have been developed which have contributed to the remarkable progress of androgen therapy. On the other hand, recently an anti-estrogen was found which specifically antagonizes estrogen and has few side effects. Additive endocrine therapy's reputation has improved with the emergence of this anti-estrogen agent. Another study has also been started on a progesterone agent which is completely different from conventional sex hormone agents. Anti-estrogen agent is widely accepted for post-operative adjuvant endocrine therapy of breast cancer taking over as the conventional post-operative adjuvant chemotherapy, and also as a partner of chemo-endocrine therapy.

Topics: Androstanols; Breast Neoplasms; Castration; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Diethylstilbestrol; Double-Blind Method; Female; Fluoxymesterone; Humans; Lymphatic Metastasis; Mastectomy; Menopause; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Testosterone

Mepitiostane (2α,3α-epithio-17β-(1-methoxycyclopentyloxy)-5α-androstane), which is a prodrug of epitiostanol (2α,3α-epitio-5α-androstane-17β-ol), is an epitiosteroid having anti-estrogenic and weak androgenic anabolic activities. The World Anti-Doping Agency prohibits the misuse of mepitiostane by athletes. Detection of the urinary metabolites epitiostanol sulfoxide and epitiostanol was studied using liquid chromatography/mass spectrometry (LC-MS) for doping control purposes. The use of LC-MS provided advantages over gas chromatography/mass spectrometry for detecting heat labile steroids because epitiostanol and epitiostanol sulfoxide were primarily pyrolized to 5α-androst-2-en-17β-ol. The method consists of enzymatic hydrolysis using β-glucuronidase (Escherichia coli), liquid-liquid extraction, and subsequent ultra-performance liquid chromatography/electrospray-tandem mass spectrometry. Epitiostanol sulfoxide was determined at urinary concentrations of 0.5-50ng/mL, recovery was 76.2-96.9%, and assay precision was calculated as 0.9-1.7% (intra-day) and 2.0-6.6% (inter-day). Epitiostanol was determined at urinary concentrations of 0.5-50ng/mL, recovery was 26.1-35.6% and assay precision was calculated as 4.1-4.6% (intra-day) and 3.3-8.5% (inter-day). The limits of detection for epitiostanol sulfoxide and epitiostanol were 0.05ng/mL and 0.10ng/mL, respectively. Epitiostanol sulfoxide and epitiostanol, as their gluco-conjugates, were identified in human urine after oral administration of 10mg mepitiostane. Epitiostanol sulfoxide and epitiostanol could be detected up to 48h and 24h after administration, respectively. The results showed that the detection window of epitiostanol is much shorter than that of epitiostanol sulfoxide. The LC-MS detection of urinary epitiostanol sulfoxide, a specific metabolite with a sulphur atom in its molecular structure, is likely to be able to identify the abuse of mepitiostane.

Topics: Androstanols; Chromatography, High Pressure Liquid; Doping in Sports; Humans; Limit of Detection; Metabolic Networks and Pathways; Molecular Structure; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Sulfoxides; Tandem Mass Spectrometry

Substitution of the steroid epitiostanol (EP) at position 17 with methoxycyclopentane yields the extremely liophilic mepitiostane (MP) with preferential partitioning into the lymph. Most of the MP in the lymph was associated with the core lipids of chylomicrons and very low-density lipoproteins (VLDL), as was also the case for EP. However, the dialysis velocity of EP and MP from lymph to plasma differed greatly; EP, but not MP, was transferred from the lymph to the plasma. This difference was attributed to differences in their unbound fraction in the lymph. Lymphatic transfer and the logP value of several tested steroids correlated well. Therefore, the oral EP prodrug, MP, partitioned into the lymph because of its superlipophilicity and resultant retention in the core lipids of chylomicrons and VLDL.

Topics: Androstanols; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry, Physical; Chylomicrons; Dialysis; Female; Lipoproteins; Lipoproteins, VLDL; Lymphatic System; Rats; Rats, Sprague-Dawley; Subcellular Fractions

Mepitiostane (MP), epitiostanol (EP), and oleic acid were administered to the jejunal loop of mesenteric vein- and thoracic duct-cannulated rats, and the intrinsic lymphatic partition rate (ILPR) of the absorbed compounds was directly determined. When 14C-EP was administered to the jejunal loop, recovery of unchanged EP in the mesenteric blood and the lymph was 7.9 and 0.03% of the administered dose, respectively. In contrast, following administration of 14C-MP, recovery of unchanged MP in the mesenteric blood and the lymph was 1.2 and 15.0%, respectively. Thus, following passage through the mucosal cell, 99.6% of the unchanged EP was partitioned into the blood and 0.4% into the lymph, while for unchanged MP, 7.6% was partitioned into the blood and 92.4% into the lymph. When 14C-oleic acid was administered to the jejunal loop, most of the penetrating oleic acid was incorporated into triglycerides in epithelial cells and transferred exclusively into the lymph. However, of the unchanged oleic acid, only 37.6% was partitioned into the lymph and 62.4% into the blood. The ILPR was 92.4% for MP, 0.4% for EP, and 37.6% for oleic acid. We conclude that the ILPR values indicate the true lymphotropic property of the compounds.

Topics: Androstanols; Animals; Bile Ducts; Female; Intestinal Absorption; Lymph; Lymphatic System; Mesenteric Veins; Oleic Acid; Oleic Acids; Rats; Rats, Inbred Strains

Pregnancy-dependent TPDMT-4 mammary tumors, characterized by requiring estrogen, progesterone, and pituitary hormones for growth, grew continuously in female DDD mice carrying pituitary isografts. The experimental model was used to investigate the antitumor effects of two p.o. steroids, mepitiostane and fluoxymesterone. When tumors implanted with pituitary isografts into the fat-pad reached palpable size, animals received 6 doses/week of 0.1, 0.3, 1.0, and 3.0 mg of either steroid intragastrically. Mepitiostane significantly suppressed tumor growth with regression in 25 and 29 percent of animals at 1.0 and 3.0 mg, respectively, but had no inhibitory effects at other doses. Fluoxymesterone retarted tumor growth during the first week of treatment at 3.0 mg but finally had no inhibitory effects at any doses. Under similar conditions ovariectomy caused tumor regression immediately, and epitiostanol, the parent steroid of mepitiostane, significantly suppressed tumor growth when given in 3 injections/week of 0.5 mg s.c. Tumous had papillary structures and almost lacked secretory activity. A comparison of these findings to those obtained with earlier generations suggests that TPDMT-4 tumors became less sensitive to the antitumor effect of epitiostanol and were able to grow at lower hormone levels with succeeding generations. Morphologically, progression to more cancer and less secretory activity was noticed.

Topics: Androstanes; Androstanols; Animals; Antineoplastic Agents; Body Weight; Castration; Female; Fluoxymesterone; Male; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Neoplasm Transplantation; Organ Size; Ovary; Pituitary Gland; Pregnancy; Pregnancy, Animal; Sulfides; Transplantation, Isogeneic