[Nasal and nasopharyngeal cancer in animals and man]. / Rak nosa i nosoglotki u zhivotnykh i cheloveka.

This review brings together current knowledge about nasal cancer in animals and man. It must be emphasized that nasal cavity and sinus cancer (NCSC) and nasopharyngeal cancer (NPC) are different entities. NPC shows strong regional or ethnic concentration, especially Asian races have a particularly high incidence of NPC. Association of this disease with herpes virus (Epstein-Barr virus) has been made and other environmental agents such as smoking coupled with genetic predisposition, may also be involved. No suitable animal model for human NPC has been described, as most animals lack a region analogous to human nasopharynx. The histologic features of sinonasal mucosa are generally different from those of the nasopharynx. In many animals a region definitely analogous to human nasopharynx is not so obvious. The epiglottis is often functionally juxtaposed to the end of the palate and a region logically termed the pharynx may be very small or absent. Thus, the posterior nasal passage might be more legitimately considered a part of the nasal cavity. Thus, analysis of nasal area tumors within an animal species may not require a clear separation of a nasopharyngeal or epipharyngeal area, but when comparisons are made with human tumors the important specificities of nasopharyngeal pathology should be kept in mind.

Inhibition of protein-kinase-C--dependent cell proliferation of human lung cancer cell lines by the dihydropyridine dexniguldipine.

The dihydropyridine, dexniguldipine hydrochloride (B859-35), has shown therapeutic activity in experimentally induced neuroendocrine hamster lung tumors and demonstrated antiproliferative effects in a mammary cancer cell line via inhibition of Ca2+ calmodulin. Studies in NIH 3T3 fibroblasts have provided evidence that dexniguldipine may also inhibit protein kinase C (PKC). In this study, we have tested the hypothesis that dexniguldipine may inhibit the proliferation of lung cancer cells in response to autocrine or exogenous activation of PKC. Using a panel of human lung cancer cell lines, we show that dexniguldipine is a potent inhibitor of mitogenic signal transduction pathways dependent on PKC activation in several small-cell and non-small-cell lung cancer cell lines while it failed to inhibit cyclic-AMP-dependent cell proliferation.

Effect of the dihydropyridine dexniguldipine on the epidermal growth factor-stimulated proliferation of human lung cancer cell lines.

The dihydropyridine Dexniguldipine (B859-35) has been shown to inhibit calmodulin and protein kinase C in vitro, and has a significant therapeutic effect on induced neuroendocrine lung tumours in hamsters. As phase I clinical trials with this agent resulted in the development of stable disease in several patients with non-small-cell cancers and preliminary in vitro studies revealed several non-small-cell cancer cell lines susceptible to the antiproliferative effects of dexniguldipine, the possibility was investigated that this agent may inhibit cell proliferation stimulated by epidermal growth factor (EGF), which is expressed in many non-small-cell cancer types. Experiments conducted with six human lung cancer cell lines showed that dexniguldipine is a potent inhibitor of EGF-stimulated cell proliferation. This agent may therefore also be useful for the therapy of cancers that express the EGF receptor.

Ultrastructural investigations of the enterochromaffin-like (ECL) cells in three different rat strains (Sprague-Dawley, Fischer 344, Wistar) after treatment with the H+,K(+)-ATPase inhibitor pantoprazole.

The purpose of the present study was the evaluation of ultrastructural characteristics of the enterochromaffin-like (ECL) cells in the fundic mucosa of three different rat strains without treatment and after treatment with the H+, K(+)-ATPase inhibitor pantoprazole. In the study, 20 one year old female Sprague Dawley (SD), Fischer 344 (F) and Wistar (W) rats each were treated orally for three months with 4 mg pantoprazole/kg/d or with the vehicle only. The control animals showed close conformity of ECL cell density and morphology in all three strains. Treatment with pantoprazole led to a significant increase in serum gastrin concentration and GPC density in all strains. However, the electron microscopically determined ECL cell density was markedly increased in the SD strain only. Ultrastructurally all treated rats showed activation of the ECL cells, and enhanced histamine release. The SD and F strains had an enhanced proportion of large ECL cell granules, with the F rats also showing an increased granule density. In contrast, the treated W rats were found to have a lower granule density and a higher proportion of small and medium sized granules compared to their controls.

Cardiotoxicity of vasodilators and positive inotropic/vasodilating drugs in dogs: an overview.

Standard toxicological studies in dogs using high doses of vasodilators and positive inotropic/vasodilating agents give rise to a species-specific cardiotoxicity. The reason may be the extreme sensitivity of the dog to the pharmacological effects of these drugs; exaggerated pharmacodynamic effects and prolonged disturbance of homeostasis mechanisms often are responsible for the observed organ lesions. An assessment of the toxicological relevance and the risk for patients taking the drugs at therapeutic doses cannot be made without taking into account their pathomechanisms and the pathophysiological basis of the exceptional reaction patterns occurring in dogs. A large series of vasodilating and positive inotropic agents are presented, their pharmacological properties are described, and toxicological effects in dogs are compared. In view of the poor correlation between the distinct cardiac lesions induced in dogs and a lack of comparable toxicity in humans, it appears desirable to reassess the adequacy of the standard toxicological approaches for these substances.

Antiproliferative effects of the Ca2+/calmodulin antagonist B859-35 and the Ca(2+)-channel blocker verapamil on human lung cancer cell lines.

We have recently demonstrated that the dihydropyridine-derivative B859-35 has a selective chemotherapeutic effect on experimentally induced neuroendocrine lung tumors in hamsters. These tumors resembled human atypical lung carcinoids morphologically and expressed mammalian bombesin, calcitonin and neuron-specific enolase. In the hamster model, B859-35 had no antiproliferative effect on pulmonary adenomas of Clara cell origin. In this study, we have tested the antiproliferative effects of B859-35 and of the Ca(2+)-channel blocker Verapamil in vitro on three human lung cancer cell lines. The neuroendocrine cell line NCI-H727 is derived from a lung carcinoid and expresses mammalian bombesin and calcitonin. Two non-neuroendocrine cell lines are derived from peripheral pulmonary adenocarcinomas, with line NCI-H322 expressing features of Clara cells while line NCI-H358 expresses features of alveolar type II cells. B859-35 was a potent antiproliferative agent in the neuroendocrine line NCI-H727 at concentrations as low as 0.001 pM, while it inhibited cell proliferation in the two other cell lines at concentrations of 100 nM and above. Verapamil inhibited cell proliferation in the neuroendocrine line NCI-H727 at concentrations of 1 nM and above.

Diethylnitrosamine-induced metastasizing hepatocellular carcinomas in New Zealand white rabbits. A tumor model for clinical investigations.

The aim of this study was to produce large liver tumors reliably, and to diagnose the tumors during development. Therefore, New Zealand white rabbits were treated with N-nitrosodiethylamine orally three times per week by gavage and were examined by clinical-chemical assay at regular intervals during the average treatment period of 14 months. The total cumulative dose was 1200 mg N-nitrosodiethylamine over 14 months. After a short treatment period the initial dose of 3 mg/kg had to be reduced to 1.5 mg/kg. In all 11 treated animals (100%) liver tumors were seen at the end of the study. Four control animals did not show any neoplastic changes. Clinical parameters investigated were for an assessment of liver function, total protein, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin and neuraminic acid as well as some serum electrolytes. The in vivo diagnosis of liver tumors based on changes in these parameters proved to be relatively unreliable. The liver enzyme tests and urea concentration only yielded significant changes when the liver tumors were very large. Changes in neuraminic acid levels were the most reliable indicator for the presence of a liver tumor in this animal model. In the 11 treated animals, serum values of this marker increased towards the end of the study by an average of 300 mg/dl. The induced tumors were mainly hepatocellular carcinomas. Only in 1 animal was a hepatocellular adenoma found. Further primary tumors diagnosed were six adenomas in the kidneys and two uterus adenomas, as well as nasal cavity tumors (two papillomas, one carcinoma, one adenoma and one adenocarcinoma). In 70% of the treated rabbits the hepatocellular carcinomas had metastasized to the lungs.

Comparative anatomy, physiology, and function of the upper respiratory tract.

The anatomical characteristics of the upper respiratory tract of various experimental animals and man are described. There are a number of differences and similarities macroscopically and microscopically between the species. Perhaps one of the most obvious examples of anatomical differences is in the structure of the turbinates. Some of the differences could affect deposition and clearance of particles in the nasal cavities. Effects of compounds in the nasal cavity, larynx, and trachea can differ depending on the cellular composition of the mucosa.

Successful chemotherapy of experimental neuroendocrine lung tumors in hamsters with an antagonist of Ca2+/calmodulin.

The chemotherapeutic effect of B859-35, the (-)-enantiomer of dihydropyrine 3-methyl-5-3-(4,4-diphenyl-1-piperidinyl)-propyl-1,4-dihydro-2,6-dimethy l-4- (3-nitrophenyl)-pyridine-3,5-dicarboxylate-hydrochloride (niguldipine), was tested on tumors induced in Syrian golden hamsters by N-nitrosodiethylamine (DEN). Peripheral pulmonary adenomas/adenocarcinomas were induced in hamsters maintained under ambient air conditions by multiple s.c. injections of DEN for 20 weeks. We have reproducibly shown that within this time interval lung adenomas develop in a significant number of the animals. The carcinogen treatment was discontinued at this point and one group of these hamsters was given B859-35 intragastrically 5 days/week for 20 weeks while the second group of such tumor-bearing hamsters were kept for an identical time interval without further treatment. Neuroendocrine lung tumors were induced in hamsters maintained in an atmosphere of 60% O2 by multiple s.c. injections of DEN for 8 weeks. We have reproducibly shown that within this short time interval neuroendocrine lung tumors develop in a significant number of the animals. The carcinogen treatment was discontinued at this point and the animals were returned to ambient air conditions. One group of these tumor-bearing hamsters was then given B859-35 intragastrically 5 days/week for 20 weeks while a second group of these hamsters was kept untreated for an identical time interval. A control group was given s.c. injections of saline for 20 weeks under ambient air conditions. A dramatic and selective anticarcinogenic effect of B859-35 was observed on the neuroendocrine lung tumors and nasal cavity tumors induced by DEN/hyperoxia while tumors of larynx/trachea were not affected. B859-35 had no effect on peripheral adenomas/adenocarcinomas, nasal cavity tumors, papillary polyps of larynx/trachea, or liver tumors induced by DEN under ambient air conditions.