The Architecture and Function of Monoclonal Antibody-Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention.

The circulating tumor cells (CTCs) existing in cancer survivors are considered the root cause of cancer metastasis. To prevent the devastating metastasis cascade from initiation, we hypothesize that a biodegradable nanomaterial loaded with the abortifacient mifepristone (MIF) and conjugated with the epithelial cell adhesion molecule antibody (aEpCAM) may serve as a safe and effective cancer metastatic preventive agent by targeting CTCs and preventing their adhesion-invasion to vascular intima. It is demonstrated that MIF-loaded mesoporous silica nanoparticles (MSN) coated with aEpCAM (aE-MSN-M) can specifically target and bind colorectal cancer cells in either cell medium or blood through EpCAM recognition proven by quantitative flow cytometric detection and free aEpCAM competitive assay. The specific binding results in downregulation of the captured cells and drives them into G0/G1 phase primarily attributed to the effect of aEpCAM. The functional nanoparticles significantly inhibit the heteroadhesion between cancer cells and endothelial cells, suggesting the combined inhibition effects of aEpCAM and MIF on E-selectin and ICAM-1 expression. The functionalized nanoparticles circulate in mouse blood long enough to deliver MIF and inhibit lung metastasis. The present proof-of-concept study shows that the aE-MSN-M can prevent cancer metastasis by restraining CTC activity and their adhesion-invasion to vascular intima.

6beta-Hydroxy-5beta-methyl-20-oxo-19-norpregn-9(10)-en-3beta-yl acetate.

In the title compound, C(23)H(34)O(4), which is an intermediate in the synthesis of pregnane derivatives with a modified skeleton that show potent abortion-inducing activity, the conformation of ring B is close to half-chair due to the presence of both the C=C double bond and the axial 5beta-methyl group. Rings A and C have conformations close to chair, while ring D has a twisted conformation around the bridgehead C-C bond. Molecules are hydrogen bonded via the hydroxyl and acetoxy groups into infinite chains. Quantum-mechanical ab initio Roothan Hartree-Fock calculations show that crystal packing might be responsible for the low values of the angles between rings A and B, and between ring A and rings C and D, as well as for a different steric position of the methyl ketone side chain compared to the geometry of the free molecule.

Antiprogestagen activity of 5H-progesterone metabolites and their analogues, 16alpha,17alpha-cyclohexane-5H-pregnan-3,20-diones.

Antiprogestin activity of 5H-progesterone metabolites and their analogues 16alpha,17alpha-cyclohexan-5H-pregnan-3,20-diones was tested on rats. Modified pregnancy interruption test showed that 5alpha (H)-isomers of natural and synthetic hormones exhibit maximum activity.

[Mifepristone--a controversial drug with great potential]. / Mifepriston--et kontroversielt legemiddel med stort potensial.

BACKGROUND: Antiprogestins, agents that inhibit the action of progesterone, are among the most controversial and yet the more interesting therapeutic compounds developed over the past 20 years. MATERIAL AND METHODS: We present a review of the literature identified through limited searches on Medline, Cochrane and the Internet, with a discussion of the biological, clinical, political and ethical aspects of this important drug. RESULTS: The first effective antiprogestin in clinical use was mifepristone (also known as RU 486). This agent provides the most effective and safest means of medical abortion. It may also be used as a contraceptive and delivery-inducing agent and in the treatment of spontaneous abortion, ectopic pregnancies, leiomyoma, endometriosis, intrauterine fetal death, Cushing's syndrome and progesterone-dependent malignancies. INTERPRETATION: The introduction of mifepristone as an abortion-inducing agent has created intense political, ethical and moral controversies which have delayed clinical investigations and evaluations for potential expanded use.

Antiprogestins: mechanism of action and contraceptive potential.

Antiprogestins are characterized by substitutions at the 11 beta and 17 alpha positions of the steroid ring system and bind strongly to both progesterone and glucocorticoid receptors. Although they function predominantly as antiprogestins and antiglucocorticoids, on occasion they display progestin agonistic and even antiestrogenic properties. The most common clinical use of the antiprogestin mifepristone is to induce a medical abortion in the early stages of pregnancy. Progesterone maintains the endometrium, transforming it from a proliferative to a secretory state. It also facilitates the luteinizing hormone surge, which initiates ovulation. As a consequence, antiprogestins may also have contraceptive potential. Although antiprogestins do delay ovulation, this effect is inconsistent unless high doses are given, and under these circumstances, the antiprogestin effect is associated with unopposed estrogen action on the endometrium. Very low doses of antiprogestins do not affect hormonal secretion or ovulation or alter bleeding patterns, but they do have contraceptive potential by inducing profound alterations in endometrial morphology. Mifepristone is also a very effective and safe postcoital agent. This new class of pharmacological agents has numerous other gynecological and obstetrical indications, such as endometriosis, uterine myoma, and expulsion of the fetus in the case of fetal death in utero. Antiprogestins may also be used in the treatment of steroid-dependent tumors. There are also therapeutic implications consequent to their antiglucocorticoid properties.

PIP: Antiprogestins have a 17-alpha substitution, which promotes higher binding affinity to both progesterone and glucocorticoid receptors, and an 11-beta substitution, which appears to be responsible for the antagonistic action. Antiprogestins also exhibit progestin agonistic and even antiestrogenic properties. Induction of a medical abortion in very early pregnancy is the most frequent clinical use of the antiprogestin mifepristone (RU-486). Antiprogestins may someday be used as a contraceptive since very low doses of antiprogestins cause considerable changes in endometrial morphology. At these low doses, they do not affect hormonal secretion or ovulation or bleeding patterns. At high doses, they delay ovulation but are associated with unopposed estrogen action on the endometrium. At low doses, antiprogestins do not always delay ovulation. RU-486 is a very effective and safe postcoital contraceptive. Antiprogestins may be beneficial in treating endometriosis, uterine myoma, and steroid-dependent tumors (e.g., breast cancer). They may be used to induce labor in cases of intrauterine fetal death. Antiprogestins may prove useful in treating Cushing's syndrome due to ectopic adrenocorticotropic hormone secretion, in lowering intraocular pressure in glaucoma, and in preventing the progression of viral diseases in humans. They also appear to have even more potential benefits, such as treatment of burns.

History and perspectives of antiprogestins from the chemist's point of view.

The discovery of RU486 and its potent activity as an antiglucocorticoid and antiprogestin brought the long story on steroid hormones and antihormones to its logical conclusion. Even though scattered improvements are still possible, the armamentarium of the steroid endocrinologist is by now complete. Like any successful drug, RU486 has become the prototype of a number of analogues which are claimed to be either more active or more dissociated. The literature (mainly patients) has been searched for available data on abortive activities, and some as yet unpublished results on RU compounds have been included. It appears that a number of compounds are both more active than RU486 on a dose basis in animal studies and more dissociated in relation to a possible antiglucocorticoid activity. In addition, hydrosoluble compounds suitable for i.v. injection are available for possible development. In a longer term perspective, it cannot be excluded that potential non-steroidal antiprogestins could present additional advantages over steroidal compounds, in particular improved receptor specificity and/or reduced susceptibility to receptor mutation.

PIP: The discovery of RU-486 and its potent activity as an antiglucocorticoid and antiprogestin have brought the protracted story on steroid hormones and antihormones to a logical conclusion. For each of the five traditional classes of steroid hormones, estrogens, androgens, progestins, glucocorticoids, and mineralcorticoids, potent agonists and antagonists are available. The armamentarium of the steroid endocrinologist is therefore complete although scattered improvements do remain possible. RU-486 has already become the prototype of a number of analogs claimed to be either more active or more dissociated. The authors searched the literature for available data on abortive activities, including some as yet unpublished results on RU compounds. It appears that a number of compounds are both more active than RU-486 on a dose basis in animal studies and more dissociated in relation to a possible antiglucocorticoid activity. Moreover, hydrosoluble compounds suitable for IV injection are available for possible development. Over the long-term, it is possible that nonsteroidal antiprogestins may present additional advantages over steroidal compounds, in particular improved receptor specificity and/or reduced susceptibility to receptor mutation.

[The antiprogesterone preparation mifepristone (RU 486). Should this "abortion pill" be introduced in Denmark?]. / Antiprogesteronpraeparatet mifepriston (RU 486). Bør man indføre denne "abortpille" i Danmark?

The antiprogesterone mifepristone (RU 486) was synthesized in 1980 by Roussel-Uclaf (Paris). Since 1982 several studies have examined the ability of the drug to interrupt early pregnancies. 600 mg of mifepristone given by mouth to pregnant women with an amenorrhea of less than 50 days will lead to vaginal bleeding in more than 97% of the cases. The bleeding will be followed by moderate (menstruation-like) pain, and complete abortion will occur in 75% of the cases. A success rate of 75% is not sufficient for clinical use. The treatment should therefore consist of a combination of mifepristone and prostaglandin. The prostaglandin can be administered either by i.m. injections or as a vaginal suppository given 38-48 hours after the patient has received 600 mg of mifepristone by mouth. Such a combination of mifepristone and prostaglandin results in a complete abortion rate of more than 95%. Pelvic inflammatory disease (P.I.D.) after these abortions is extremely rare (below 0.5%), and other serious side effects are also uncommon. We find that mifepristone in combination with prostaglandin should be offered to Danish women seeking abortion as an alternative to the traditional method of vacuum aspiration.

[Synthesis of gona-3,5-dienes and studies on their activity for interruption of early pregnancy].

A series of gona-3,5-dienes were synthesized from norgestrel, norethisterone 17 alpha-hydroxyprogesterone and ethisterone via reduction of alpha, beta-unsaturated 3-ketones to allylic alcohols and dehydration with concomitant migration of the double bond. The structures of these gona-3,5-dienes were verified by MS and 1H-NMR spectral data. Pharmacological results showed that compound IVb2 in this series gave rise to significant interruption of early pregnancy in mice. The mechanism of the early pregnancy terminating effect of this compound was discussed.