China
Africa
Explore chapters and articles related to this topic
Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Rather than testosterone itself, prostatic cancer is mainly driven by dihydrotestosterone (DHT, also known as androstanolone or 5α-androstan-17β-ol-3-one), which is produced mainly in the prostate, testes, hair follicles, and adrenal glands by the action of the enzyme 5-α-reductase on testosterone produced by the testes (Figure 8.19). In men, approximately 5% of testosterone undergoes 5α-reduction to DHT which has 2–3 times greater affinity for the Androgen Receptor than testosterone and 15–30 times greater affinity than the adrenal androgens. Thus, one obvious form of treatment involves removal of the DHT stimulus which can be achieved either by ablating its precursor (i.e., testosterone) or by blocking its action at the receptor. The former approach used to be achieved by surgical removal of the testes (bilateral subcapsular orchidectomy), and this is still carried out in patients who are not suitable for other therapies. However, orchidectomy has largely been replaced by endocrine therapies, including the gonadorelin agonists (e.g., goserelin, buserelin, leuprorelin, triptorelin or histrelin) and antagonists (e.g., degerelix), the anti-androgens, and the estrogens, all of which are described below. It is noteworthy that 5-α-reductase inhibitors are not used to treat prostate cancer as, even if DHT could be ablated, testosterone itself would still drive the tumor. However, such inhibitors (e.g., dutasteride [AvodartTM] and finasteride [ProscarTM]) are used to reduce prostate size in benign prostatic hyperplasia (BPH) to improve urinary flow rate and other obstructive symptoms. Conversion of testosterone (produced by the testes) into dihydrotestosterone (DHT) by the enzyme 5-α-reductase within prostate tumor cells. DHT binds to the androgen receptor (AR) with a higher affinity than testosterone itself.
Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Alessio Nocentini, Alessandro Bonardi, Paola Gratteri, Bruno Cerra, Antimo Gioiello, Claudiu T. Supuran
The ubiquitous hCA II and tumor-associated hCA IX were comparably inhibited by carboxylic acids 1–6, 8–10, sulfonic acid 7 and phenols 19, 20 in the micromolar range spanning between 38.9 and 89.9 µM. Tauroursodeoxycholic acid (7) stands out as the most efficient hCA IX inhibitor, being instead its action the least efficient against hCA II. Repositioning of the alcoholic moieties mainly located at the outer edge of the molecular structures has been shown to slightly alter the weak inhibition profiles. The lengthening of the carboxyalkyl chain of ursodeoxycholic acid (5) by a glycine unit as in 6 does not affect the derivatives efficacy against both considered isoforms. Reduction of the enone system at ring A of testosterone (13) to 5α-steroids androstanolone (16) and androsterone (14) does not interfere with the hCA II and IX inhibitory efficacy.
Analysis of the urinary metabolic profiles in irradiated rats treated with Activated Protein C (APC), a potential mitigator of radiation toxicity
Published in International Journal of Radiation Biology, 2023
Shivani Bansal, Sunil Bansal, Brian L. Fish, Yaoxiang Li, Xiao Xu, Jose A. Fernandez, John H. Griffin, Heather A. Himburg, Marjan Boerma, Meetha Medhora, Amrita K. Cheema
At day 14, rat 3K3A variant of APC was most effective in partially restoring urinary metabolic levels to near-normal abundance for the metabolites including tryptophan, PRPP, nicotinuric acid, 15S-HpEDE, 9-OH-PGF2α, while rat WT mitigated the effects of IR on PRPP, Trp, 15S-HpEDE. Human WT APCs treatment managed to recover the levels of 11-DHC, PKC-substrate to near normal at day 14 post IR (Supplementary Table 5). Rat 3K3A also induced a total recovery for androstanolone at 30 d. Pathway analysis revealed that rat 3K3A APC impacted the valine, leucine, and isoleucine degradation, C21-steroid hormone biosynthesis and metabolism post 14-days treatment with rat 3K3A APC (Figure 4(C)).