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.     

Crosstalk in transition: the translocation of Akt

Journal of Mathematical Biology - Akt/PKB is an important crosstalk node at the junction between a number of major signalling pathways in the mammalian cell. As a significant nutrient sensor, Akt...     

The effect of pressure on the electrical breakdown in the membranes of Valonia utricularis

The interpretation of electrical breakdown in terms of electro-mechanical instabilities, predicts that the breakdown potential should decrease with increasing cell turgor pressure.Experiments were conducted to test this hypothesis on cells of Valonia utricularis over a turgor pressure range of 0.5 · 10⁵–5.0 · 10⁵ N/m². Electrical breakdown was measured using intracellular electrodes and 500 μs current pulses. The pressure was monitored by an intracellular micropipette pressure transducer. The results obtained show a linear decrease in the critical breakdown potential with pressure. The effective compressive modulus of the cell membrane, γ, is calculated from the slope of this line to 69 ± 10 · 10⁵N/m² (average value of seven measurements). This is consistent with the theoretical prediction of the electromechanical model using our previously determined values of the elastic modulus of the membrane.A theoretical analysis is given of the effects of pressure on the breakdown. This includes also considerations of the indirect effect of pressure on the membrane via stretching of the cell wall with a possible coupling of such strains to the cell membrane. The results and analysis presented allow us to conclude on the basis of the experimentally determined breakdown P.D. of 959 mV that the region of membrane where electrical breakdown occurs is a dielectric with one of the following combinations of parameters: (A) a thickness δ = 7–9 nm with a dielectric constant ? = >10, e.g. a hydrated protein spanning the whole membrane. (B) δ = 4–5 nm with ? = 3–8, e.g. a lipoprotein of lipid bilayer dimensions. (C) δ ≈ 2 nm with ? = 2–3, e.g. a half lipid bilayer.If we assume that the breakdown P.D. of the tonoplast and plasmalemma are identical, that is 480 mV, then there is only one reasonable choice for the membrane thickness and the dielectric constant: δ = 2nm, ? = 3–8, e.g. a (lipo-)proteinaceous module facing a half lipid bilayer.     

Determination of parameters of the survival curve of the stem cells of the intestinal crypts by LD50 and the regenerated crypt count. Determination of the RBE of p(65) + Be neutrons

The early effects of an irradiation on the intestinal epithelium have been evaluated, at the tissular level, by LD50 after single and multifraction irradiation, and, at the cellular level, by numeration of the regenerated intestinal crypts (Withers technique) after a single fraction irradiation. From the set of informations provided by both criteria, one derived the values of the parameters defining the survival curve of the intestinal clonogenic crypt cells after irradiation by gamma-rays (two component model): D0 = 1.5 Gy, 1D0 = 4.5 Gy, nD0 = 2.25 Gy and n = 20. In other respects, the p(65) + Be neutrons RBE (ref. 60-Cobalt) after a single fraction irradiation is equal to 1.75 +/- 0.2 and 1.64 +/- 0.25 for the LD50 at the 5th day and for the regeneration of 50 crypts after 3.5 days respectively.     

Combination of chemotherapy and radiotherapy. I. Differential effect on the intestinal syndrome of irradiation combined with the drug administered in fractional doses and at various times]

We have studied the different effects on the intestinal syndrome between the administration of fractional doses of 5-Fu before and after irradiation. There is no difference between the diverse modalities and we obtain the same result when the 5-Fu is administered, fractionated or not, before or after the irradiation.