P450-dependent enzymes as targets for prostate cancer therapy

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all the patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy.

Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer.

In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve a maximal androgen ablation with a single drug treatment. Ketoconazole at high dose blocks both testicular and adrenal androgen biosynthesis but its side-effects, mainly gastric discomfort, limit its widespread use. A series of newly synthesized, more selective, steroidal 17,20-lyase inhibitors related to 17-(3-pyridyl)androsta-5,16-dien-3β-ol, may open new perspectives in this field.

In prostate cancer patients who relapse after surgical or medical castration, therapies aiming at suppressing the remaining adrenal androgen biosynthesis (ketoconazole) or producing a medical adrenalectomy (aminoglutethimide + hydrocortisone) have been used, but are becoming obsolete with the generalization of maximal androgen blockade in first line treatment. The role of inhibition of aromatase in prostate cancer therapy, which was postulated for aminoglutethimide, could not be confirmed by the use of more selective aromatase inhibitors, such as formestane.

An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In vitro, it enhances the antiproliferative and differentiation effects of RA in cell lines that express RA metabolism, such as F9 teratocarcinoma and MCF-7 breast carcinoma cells. In vivo, monotherapy with LIA increases RA plasma levels and, to a greater extent, endogenous tissue RA levels leading to retinoid-mimetic effects. In the rat Dunning prostate cancer models, it inhibits the growth of androgen-independent as well as androgen-dependent carcinomas relapsing after castration. Concurrently, changes in the pattern of cytokeratins characteristic of increased differentiation were observed. Early clinical trials show that LIA, in second or third line therapy in metastatic prostate cancer, induces PSA responses in about 30% of unselected patients. In some patients regression of soft tissue metastasis has been observed. In a subgroup of patients, an important relief of metastatic bone pain was also noted.     

Hematologic parameters of the white donkeys of Asinara]

In 14 albino donkeys (6 males and 8 females) aged 1-12 years, about 25% of the whole population, 30 blood parameters were determined, with automatic equipment, monthly, for 4 months. No significant differences between sexes or compared with other donkey breeds were found, in spite of the particular characteristics of the population and of their environment.     

DNA measurements of cervical epithelial cells in combination with scanning electron microscopy

A method is described in which the surface morphology of benign and malignant cervical cells is investigated with a combined light microscope-scanning electron microscope, after the measurement of the DNA content of each individual cell in the same instrument. The suspect cells can thus be identified by an increased aneuploid DNA content (greater than 5C) and not primarily by morphology. The DNA content was measured, after a quantitative acriflavine-Feulgen staining, by using a microphotometer attached to the combined microscope. It was found that the suspect cells show a different surface morphology compared to normal cells from a benign specimen.     

Une dent d'aspect mammalienen provenance du Rhétien Français

This paper analyses a tooth with mammal-likecharacters found in the lower Rhaetian of Lorraine. The comparison of this specimen with teeth of therapsid cynodonts and contemporary mammals has not led us to assimilate it to any previously known form, but suggests a relationship with late and advanced cynodonts, and allows us to place the animal at the reptilian-mammalian transition. This is the first indication of a therapsid in France.     

Experimental studies with liarozole (R 75,251): an antitumoral agent which inhibits retinoic acid breakdown.

Liarozole reduced tumor growth in the androgen-dependent Dunning-G and the androgen-independent Dunning MatLu rat prostate carcinoma models as well as in patients with metastatic prostate cancer who had relapsed after orchiectomy. In vitro, liarozole did not have cytostatic properties, as measured by cell proliferation in breast MCF-7 and prostate DU145 and LNCaP carcinoma cell lines. It did not alter the metabolism of labeled testosterone i.e. the 5 alpha-reductase in cultured rat prostatic cells. In mouse F9 teratocarcinoma cells liarozole did not show any retinoid-like properties but enhanced the plasminogen activator production induced by retinoic acid. Furthermore, liarozole and retinoic acid similarly reduced the growth of the androgen-dependent Dunning-G tumor in nude mice and inhibited tumor promotion elicited by phorbol ester in mouse skin. These data have raised the hypothesis that the antitumoral properties of liarozole may be related to inhibition of retinoic acid degradation, catalyzed by a P-450-dependent enzyme that is blocked by the drug.     

Qualitative aspects of palmar dermatoglyphics in a sample of Sardinian population

The author examines certain qualitative aspects of palmar dermatoglyphics in 820 individuals of both sexes from the city of Cagliari (Sardinia). The overall results obtained are discussed and the sexual and lateral differences are considered. The sample examined differs from other Mediterranean samples because of a tendency toward a vertical trend of the papillary lines, a lower frequency of patterns in the 2nd and 3rd interdigital areas and a higher frequency of patterns in the 4th interdigital area.     

Is self-compatibility the main breeding system in borage (Borago officinalis L.)?

The polygenic postzygotic self-incompatible system reported in borage (Borago officinalis L.) is refuted. The behaviour of pollen tubes after self- and cross-pollination, analysis of the crossability coefficient, seed set after continuous generations of self-pollination and the effects of inbreeding depression in borage were studied. Evidence of self-compatibility was established. The influence of protandry in a self-compatible system is also discussed. Received: 15 July 1999 / Accepted: 3 November 1999     

Parvalbumin-immunoreactive neurons in the entorhinal cortex of the rat: localization,morphology, connectivity and ultrastructure

Brain Cell Biology - We studied the distribution, morphology, ultrastructure and connectivity of parvalbumin-immunoreactive neurons in the entorhinal cortex of the rat. Immunoreactive cell bodies...     

Seasonal changes in blood testosterone in the Giara horse

The blood testosterone changes in three Giara stallions, average age 8 years old and average weight 183 Kgs, were checked weekly for a year using a radioimmunological method. The horses showed a highly seasonal hormonal activity concentrated in the first half of the year (winter and spring). In the second half of the year (summer and fall) the stallions showed low levels of testosterone. The highest level of the androgen hormone occurred in April, the lowest in October. The absolute levels of this hormone agreed substantially with the relative literature.