Angiogenesis is continuous with two peaks during azaserine-induced rat pancreatic adenocarcinoma progression: an electron microscopic morphometrical study.

Although the indispensable role of neoangiogenesis in tumour growth became generally accepted, quantitative microvascular changes associated to tumour progression have been followed only in a few experimental models. In our study a further experimental system, the azaserine-induced rat pancreatic adenocarcinoma was applied for this purpose. The 15-20 month long progression of this tumour provides us a special opportunity to dissect multistage carcinogenesis in different respects. Tumour samples were taken at months 6, 8 (early lesions), 10, 13, 15 (adenomas), and 20 (differentiated and anaplastic adenocarcinomas) and identified by semithin section histology. We applied reliable and reproducible electron microscopic morphometry for quantification of capillary volume and surface densities in unit tissue volume. Correlation of microvessel volume (MVVD) and surface (MVSD) density data indicated that their changes were the consequence of the changing balance between tumour growth and neoangiogenesis. The significantly decreased but persistent size of the tumour microvasculature during the early slow premalignant growth (months 6-10) is indicative for a slow, but continuous balanced angiogenesis. A dramatic MVVD and MVSD increase at month 13 and the consecutive decrease measured in month 15 adenomas depicted a hitherto unprecedented angiogenic wave within the month 10-15 premalignant growth period. The size of the tumour microvasculature became again stabilized below the control level for the next 5 months of slow growth during which, however, several differentiated adenocarcinomas were transformed to fastly growing angiogenic anaplastic carcinomas, some of which gave rise to invasive tumours. These findings once again verify the angiogenic switch theory.

Potency and specificity of the pharmacological action of a new, antiasthmatic, topically administered soft steroid, etiprednol dicloacetate (BNP-166).

In the present study, the pharmacological effects of etiprednol dicloacetate (BNP-166; ethyl-17alpha-dichloroacetoxy-11beta-hydroxyandrosta-1,4-diene-3-one-17beta-carboxylate), a new soft steroid, intended to use for the treatment of asthma, were investigated in an animal model of allergen sensitized and challenged Brown Norway rats using local treatment. The examinations involved the determination of the effect of the compound on the extent of allergen induced broncho-alveolar fluid and lung tissue eosinophilia, goblet cell hyperplasia and mucus production, perivascular edema formation, and airways hyperresponsiveness. The activity of etiprednol dicloacetate was compared with that of budesonide. Using in vitro methods, the soft character of etiprednol dicloacetate was investigated together with its capability to dissociate transrepressing and transactivating properties. We found that combining all the examined parameters etiprednol dicloacetate was at least equipotent with budesonide in the animal model, but in several investigated variables it surpassed the activity of budesonide. The effect of etiprednol dicloacetate in vitro was shown to be the function of the quantity of the serum, present in the assay, it was also strongly affected by the incubation time and decreased significantly when it was preincubated with human plasma. These features are characteristics of a soft drug that is quickly inactivated in the systemic circulation. In addition, it was revealed that while the transrepressing potential of etiprednol dicloacetate remained high, its transactivating activity was greatly reduced. These data indicate that the strong local effect of the compound will very likely be accompanied with a significantly reduced systemic activity predicting favorable selectivity in the pharmacological action of etiprednol dicloacetate.

Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation.

The knowledge of alterations in regulation of autophagy during tumorigenesis may also help our understanding of its normal control. We established an experimental system and reported recently that autophagic capacity, measured as the cell's capability of increasing segregation (formation of autophagosomes) and subsequent degradation of cytoplasmic quanta were highly increased in premalignant nodule cells 6 months after initiation by azaserine in the rat pancreas in vivo. In the present study, we followed changes of these autophagic functions throughout the tumour progression. We carried out electron-microscopic morphometrical analysis of the expansion of autophagic vacuole compartment and subcompartments induced by vinblastine (an in vivo segregation enhancer), as well as their regression upon segregation-inhibitor cycloheximide post-treatment. Premalignant tumour samples were taken at month 5, month 8 (nodules), month 10 and month 15 (adenomas) after initiation. In all these stages, a highly increased and varying autophagic capacity was found compared with the host tissue. The basal (non-stimulated) autophagic compartment was measurable only at month 5 and month 15, and its regression upon cycloheximide was consistent with increased basal autophagic activity. Compared with the host tissue, autophagic capacity profoundly decreased in the differentiated and anaplastic adenocarcinomas at month 20, when, surprisingly, cycloheximide was unable to inhibit segregation. Our conclusion is that down-regulation of the cycloheximide sensitive segregation and a partly compensatory up-regulation of an alternative pathway of segregation might occur along with malignant transformation.