Preclinical comparison of mTHPC and verteporfin for intracavitary photodynamic therapy of malignant pleural mesothelioma

Efficacy and tumour selectivity of photodynamic therapy with two clinically approved sensitizers (mTHPC, verteporfin) were assessed for focal intracavitary photodynamic therapy (PDT) in rodents with malignant pleural mesothelioma (MPM) at recommended drug-light conditions and at escalating sensitizer dosages. MPM tumours were generated in 15 Fischer rats by subpleural mediastinal tumour cell injection followed after 5 days by intracavitary PDT with light delivery monitored by in situ dosimetry. Animals were intravenously sensitized either with mTHPC (0.1 mg/kg, n = 3; 0.2 mg/kg, n = 3) followed after 4 days by illumination with 20 J/cm(2) at 652 nm, or with verteporfin (0.6 mg/kg, n = 3; 1.2 mg/kg, n = 3) followed after 20 min by illumination with 100 J/cm(2) at 689 nm. Three untreated tumour-bearing animals served as controls. Histological evaluation of the treated tumour and of adjacent normal organs was performed 10 days after tumour implantation. The extent of PDT-induced tumour necrosis was compared to the non-necrosed area and expressed in percentage. A locally invasive growing MPM tumour (3.1 +/- 1 mm diameter) without spontaneous necrosis diameter was found in all animals. For both sensitizers, focal intracavitary PDT was well tolerated at drug-light conditions recommended for clinical applications. Mediastinal organs were spared for both sensitizers but verteporfin resulted in a higher extent of tumour necrosis (80%) than mTHPC (50%). Drug dose escalation revealed a higher extent of PDT-related tumour necrosis for both sensitizers (mTHPC 55%, verteporfin 88%), however, verteporfin-PDT was associated with a higher toxicity than mTHPC-PDT.     

Malignantly transformed non-parenchymal liver epithelial cells and transformed oval cells suppress the homotypical gap junctional intercellular communication of co-cultured rat liver parenchymal cells

Isolated rat liver parenchymal cells (PC) were co-cultured witha non-parenchymal rat liver epithelial cell line (NEC) or withan oval cell line. The homotypical gap junctional intercellularcommunication (GJIC) between the liver PC was measured aftermicroinjection of Lucifer Yellow by dye transfer. The rat liverPC were dye coupled between 87% and 100% for at least 1 weekin both co-cultures, in contrast to PC in monoculture betweenwhich no dye coupling was left after 1 week. When liver PC wereco-cultured with a transformed and tumorigenic NEC or with atransformed and tumorigenic oval cell line the homotypical GJICbetween the liver PC was drastically decreased with culturetime, and the PC were then compressed and displaced by the expansivegrowth of the transformed cell lines. The disturbance of theGJIC between normal cells by adjacent tumorigenic cells mightbe a new mechanism to explain the expansive growth of tumors.     

Relationships Between Gastric Emptying and Intestinal Absorption of Nutrients and Energy in Mini Pigs

Little is known about the relationship betweengastric emptying of nutrients regulated by feedbackmechanisms and the absorptive capacity of the gut.Therefore, we wanted to elucidate theseinterrelationships. A 150-cm jejunal segment was perfused (1-8kcal/min) with three different nutrient solutions(either 60% of energy as carbohydrate, or 60% asprotein, or 33.3% of each nutrient). In separateexperiments, gastric emptying was measured afteradministration of three different meals with the samenutrient composition as the perfusion solutions. Thejejunal absorption of carbohydrate, protein, fat, andenergy demonstrated saturation kinetics. The kineticsdiffered among the three nutrients; carbohydrates wereabsorbed at higher rates than fat and protein.Interactions among the nutrients altered the kinetics providing a constant absorption of energy.After meals, the stomach emptied equal amounts of energydespite large variations in meal composition. Theavailable intestinal absorptive capacity for protein was utilized by 96%, whereas that forcarbohydrate, fat and energy were utilized only by46-62%. Besides reserves in the absorptive capacity, theintestine provided reserves in total length available for absorption. The results indicate a closerelationship between the energy-dependent absorption ofnutrients and the energy-dependent feedback inhibitionof gastric emptying.