In vitro and in vivo models for the evaluation of potent inhibitors of male rat 17alpha-hydroxylase/C17,20-lyase.

The C(17,20)-lyase is a key enzyme in the biosynthesis of androgens by both the testes and adrenals. A complete inhibition of this enzyme would provide an alternative means of androgen suppression for the treatment of prostatic cancers. In the present study, the inhibitory effects of new non-steroidal compounds were tested in vitro on rat C(17,20)-lyase versus abiraterone, a reference steroidal inhibitor. Their activities were also evaluated in vivo on plasma testosterone (T) and luteinizing hormone (LH) levels and on testes, adrenals, seminal vesicles (SV) and ventral prostate (VP) weights after 3 days of oral treatment to adult male rats (50mg/kg per day p.o.). Inhibition in the nanomolar range was obtained with TX 977, the lead racemate product in this series, and optimization is ongoing based on a slight dissociation observed between its two diastereoisomers, TX 1196-11 (S) and TX 1197-11 (R). These non-steroidal compounds (including YM 55208, a reference competitor) proved to be more active in vivo than abiraterone acetate in this model, but the observed impact on adrenal weight suggests that the specificity of lyase inhibition versus corticosteroid biosynthesis deserves further investigations with this new class of potentially useful agents for the treatment of androgen-dependent prostate cancer.

In vitro and in vivo models for the evaluation of new inhibitors of human steroid sulfatase, devoid of residual estrogenic activity.

The goal of our research project is to develop a new class of orally active drugs, estrone sulfatase inhibitors, for the treatment of estrogen-dependent (receptor positive) breast cancer. Several compounds were synthesized and their pharmacological potencies explored. Based on encouraging preliminary results, three of them, TX 1299, TX 1492 and TX 1506 were further studied in vitro as well as in vivo. They proved to be strong inhibitors of estrone sulfatase when measured on the whole human JEG-3 choriocarcinoma and MCF-7 breast cancer cells and their IC(50)s found to be in the range of known standard inhibitors. Their residual estrogenic activity was checked as negative in the test of induction of alkaline phosphatase (APase) activity in whole human endometrial adenocarcinoma Ishikawa cells. In addition, their effect on aromatase activity in JEG-3 cells was also examined, since the goal of inhibiting both sulfatase and aromatase activities appears very attractive. However, it has been unsuccessful so far. Then, in vivo potencies of TX 1299, the lead compound in our chemical series, were evaluated in comparison with 6,6,7-COUMATE, a non-steroidal standard, in two different rat models and by oral route. First, the absence of any residual estrogenic activity for these compounds was checked in the uterotrophic model in prepubescent female rats. Second, antiuterotrophic activity in adult ovariectomized rat supplemented with estrone sulfate (E(1)S), showed that both compounds were potent inhibitors, the power of TX 1299 relative to 6,6,7-COUMATE being around 80%. This assay was combined with uterine sulfatase level determination and confirmed the complete inhibition of this enzyme within the target organ. Preliminary studies indicated that other non-steroid compounds in the Théramex series were potent in vitro and in vivo inhibitors of estrone sulfatase in rats and further studies are in progress.

Primary structure of a chitinase-encoding gene (chi1) from the filamentous fungus Aphanocladium album: similarity to bacterial chitinases.

Chitinase 1 (Chi1) is the major extracellular chitinase from the hyperparasitic fungus, Aphanocladium album. We determined the complete sequence of the chromosomal and cDNA copies of the structural gene (chi1) coding for Chi1. The coding region is interrupted by three short introns (55, 53 and 49 bp long). Chi1 is 423 aa long and begins with a stretch of 34 aa not found in the mature protein. The Chi1 sequence presents overall similarities with bacterial chitinases from Serratia marcescens and Bacillus circulans. Compared with other chitinases, A. album Chi1 has only two short similarity regions (12 and 8 aa long), which are also found in bacterial, yeast and some plant chitinases.

Phylogeny of some Fusarium species, as determined by large-subunit rRNA sequence comparison.

Fifty-two strains from eight species of Fusarium were analyzed by rapid rRNA sequencing. Two highly variable stretches (138 and 214 nucleotides) of the 5' end of the 28S-like rRNA molecule were sequenced. Such stretches permit evaluation of the divergence between closely related species and even between varieties within a species. The phylogenetic tree computed from the number of nucleotide differences shows seven Fusarium species to be more closely related to one another than the eighth species, F. nivale, is to them. On the basis of these data, we discuss both the phylogenetic value of taxonomical criteria and the impact of our findings on the demarcation of the genus Fusarium. We conclude that this method is suitable for establishing a precise phylogeny between closely related species within a genus.

Brainstem lesions due to granular ependymitis in symptomatic diffuse esophageal spasm: a case report.

An 80 year-old man had symptomatic diffuse esophageal spasms for a few months. They were documented by radiographic, endoscopic and manometric findings. The post-mortem neuropathological examination showed a granular ependymitis of the fourth ventricle involving the dorsal region of the motor dorsal nuclei of the vagus nerve which showed frank neuronal loss. The muscular wall of the esophagus, its myenteric plexus and the fasciculi of the vagus nerve were histologically normal. This is the first published case of such a brainstem lesion associated with symptomatic diffuse esophageal spasms. These pathological data are compared with those already published on achalasia.

[Compressive tuberculous lymphadenitis of the common bile duct: spontaneous recovery by fistulization in the choledochus]. / Adénopathie tuberculeuse compressive de la voie biliaire principale: guérison spontanée par fistulisation dans le cholédoque.

The authors report the case of a 26 year old man who presented with jaundice after an operation for peritoneal and ileal tuberculosis. Abdominal sonography, CT Scan and endoscopic retrograde cholangio-pancreatography showed that the jaundice was due to the compression of the common bile duct by tuberculous lymph nodes. This compression disappeared after spontaneous fistulisation into the common bile duct. The review of the literature shows that this localisation of tuberculous lymphadenitis is uncommon and is rarely diagnosed before laparotomy. Antituberculous therapy alone is generally not sufficient and should be associated with surgical treatment.