Old scars of the pleura, for example from chronic empyema or therapeutic pneumothorax, can cause a malignant mesothelioma appearing some decades later. The authors describe two cases of primary pleural tumors, which probably had such an etiology. A literature review revealed 20 further cases, the majority of which were squamous cell carcinomas. Whether these tumors developed from metaplastic mesothelium or inplanted cells from the skin is not clear.

We recently reported that a high amount of ammonia was produced in the culture medium of H35 hepatoma cells in reponse to ionising radiation (Van Rijn et al, 2003). As a result of hyperammonia and the accompanying pH increase, surviving cells failed to develop into colonies at high inoculation densities. The expected clonogenic potential of the cells reverted to more normal levels when the culture medium of irradiated cultures was replaced by a fresh medium halfway through the postexposure period. Even so, colonies were reduced in size. The removed medium proved cytotoxic to nonirradiated cells, indicating that irradiation per se was not responsible. Analysis of the medium implicated ammonia as the primary cytotoxic compound. Endogenously produced ammonia gas acts like a free radical, and is very aggressive and cytotoxic until it is converted into ammonium ions, which cells can tolerate at millimolar levels. Since native ammonia produces alkalinity, raised pH also accounts for cell death. Parallel with the development of hyperammonia, ornithine and citrulline levels were raised, whereas arginine was lost from the medium. Thus, this minimal deviation hepatoma seemed to be able to convert ammonia into urea through a fully functional ornithine cycle. This was thrown in doubt when it was established that the cells did not proliferate when ornithine was added in place of arginine. Replacement of arginine by citrulline, on the other hand, worked well and also prevented the development of hyperammonia (Van Rijn et al, 2003).The accumulation of ornithine in the medium and a report on the induction of ornithine decarboxylase by ionising radiation (Grassilli et al, 1995) pointed to the possibility that polyamines were involved in the formation of ammonia. Furthermore, since the medium toxicity was not fully explained by the presence of ammonia and cell death appeared to be apoptotic (Van Rijn et al, 2003), the idea was advanced that the cytotoxicity was partly due to disturbance of polyamine homeostasis (Schipper et al, 2000). An excess of polyamines then could be a potential source for the ammonia (Seiler, 2000).Investigation of the synthesis and interconversion pathways of the diamine, putrescine, and the polyamines, spermidine and spermine was undertaken. Several inhibitors are known to interfere with the key enzymes, ornithine decarboxylase and Sadenosylmethionine decarboxylase, or the diamine-and polyamine oxidases. Many of the inhibitors, for example, a-difluoromethylornithine, L-agmatine, dicyclohexylamine, methylglyoxalbis-guanylhydrazone and CGP48664A, reduced the release of ammonia. Conversely, the addition of the depleted product (putrescine, spermidine or spermine) or of inhibitors of the diamine/polyamine oxidases (aminoguanidine and MDL72527) restored hyperammonia. However, any suppression of the hyperammonia development was accompanied by a decreased conversion of arginine into ornithine and citrulline. Furthermore, most of the inhibitors except L-agmatine reduced the clonogenic survival in the combination ...

No abstract