No abstract

Porphobilinogen deaminase (PBGD), one of the enzymes in the pathway of heme synthesis, was found to be elevated in peripheral mononuclear cells of 60% of patients with epithelial tumors and metastatic spread, but only in 14% of patients with tumor and no evidence of metastases. The combination of both high lactic dehydrogenase and high PBGD afforded a sensitivity of 40%, but a specificity of 96% in diagnosing metastatic spread.

The stimulation of protoporphyrin (PP) biosynthesis in 816 melanoma cells in order to facilitate photodynamic cell killing was studied. Biosynthesis and accumulation of PP in the melanoma cells was increased from 8 to 15 pmol/mg protein by the use of dimethyl-sulfoxide (DMSO), a diflerentiation-inducer. Treatment of the cells with the porph-nic agent allylisopropyl-acetamide (AIA) stimulated an additional PP increase. The most remarkable enhancement of intmcellular PP was achieved by the supplementation of 5-aminolevulinic acid (5-AlA) to the growth medium following the addition of DMSO and AIA duringthe induction phase. The intracellular concentration of PP exceeded 21 950 pmol/mg protein following combined stimulation by DMSO/AIA and 5-AIA. The porphyrins produced in the incubated cells, in serum-depleted medium, consisted of 95% PP; 88% of it was recovered from the cells and only 7% was excreted into the medium. Photosensitization of the B 16 melanoma cells containing high PP concentrations was effective even at low light doses. Potassium (K) efflux was the first measurable si of cell damage determined by X-ray microanalysis ( X d ) following fast liquid-nitrogen fixation. During a I min interval, 7096 of cellular K was lost. After 5 min illumination, complete cell destruction was detected by scanning electron microscopy (SEM) and XRMA The photodamaged cells showed influx of Na, CI and Ca ions accompanying the immediate K losses. Ultrastructural cell damage was manifested by disintegration of the outer membrane. Total cell death of B I 6 melanoma cells was achieved by chemical induction of endogenous PP and photosensitization. 8 1994 Wilq-Liss, Inc.

SummaryPregnant rats, treated with high doses of propranolol, gave birth to small for dates neonates. Litter size was affected in daily doses of 100 and 150 mg/kg/day. Propranolol markedly influenced the gain in weight normally observed in pregnant rats. The placentas of the rats which received the higher doses of propranolol weighed about 30% less than normal placentas. SpeculationPregnant rats, treated with propranolol, gave birth to small for dates neonates. This effect is possibly the result of a drug-induced reduction in transport across cellular membranes, resulting in malnutrition. Since similar effects were reported in humans, treatment with propranolol during pregnancy should be further reevaluated in laboratory animals.The administration of propranolol to pregnant women is slowly gaining acceptance. If the present trend continues it will possibly become one of the more extensively used drugs for a variety of conditions associated with pregnancy such as: Lypertension (2,6), hyperthyroidism (1, 12), cardiac arrhythmias (13,16,20), and hypertrophic obstructive cardiomyopathy (5,7,25). A relatively laree number of side effects on the Drocess of ~arturition and on Y 1 1 the newborn have been reported. One of these side effects is intrauterine growth retardation (2, 6, 16) often accompanied by a small or fibrotic placenta (6, 16). These findings are thought to be caused by sustained increase in uterine muscle tone or hemodynamic changes in the mother and in the fetus resulting from Padrenoceptor blockade by propranolol(l6). In previous investigations we have shown that high concentrations of propranolol partially inhibit the uptake of amino acids (17, 18), uridine and thymidine (19), and 2-deoxyglucose (3) by chick embryo liver cells in vitro. Preliminary experiments indicate that the same inhibition may occur in mammalian cells, both in vitro and in vivo. This creates a situation analogous to starvation, which would exert its effects mainly on rapidly dividing cells or tissues with a hiah metabolic rate.Propranolol cFosses the mammalian placenta (14) and its pharmacologic effects on the fetus are easily demonstrated (9, 10). In view of our previous laboratory findings and the reports of small placentas and fetuses in women receiving propranolol during pregnancy, a methodical investigation on the effects of this drug in pregnant rats was initiated. MATERIALS AND METHODS ANIMALSThe experiments were carried out using Wistar rats, randomly bred, and weighing 140-160 g. Timed pregnant rats were obtained by mating virgin females with experienced male rats for a 24-hr period. dl-Propranolol was administered starting the morning after impregnation.Oral administration of dl-propranolol was achieved by dissolving the drug in the water imbibed by the rats. The concentrations of propranolol in the drinking water were based upon long term measurements of the average consumption of water containing propranolol per rat per 24 hr, which was found to be about 25 & 7 ml/day. The concentrations were such that each group of ra...