PDGF AA as mediator in nicotine-dependent carcinogenesis

Effect of nicotine on PDGF AA and PDGF BB interaction with cervicalcancer SiHa cells was tested. [¹²⁵I]PDGF AA was internalizedby cells and accumulated in the cytoplasm and nucleus (chromatin).In the absence of nicotine, maximal accumulation of [¹²⁵I]PDGFAA inside the cells occurred after 1 day of incubation, whichwas followed by a progressive degradation of the growth factorduring the next 2, 3 and 5 days of cell exposure. In the presenceof 0.001 or 0.01% nicotine, accumulation of [¹²⁵I]PDGF AA wasslightly higher than in the absence of nicotine, and maximalaccumulation occurred after 2 days of incubation. In the presenceof 0.1% nicotine, maximal accumulation occurred after 5 daysof incubation and was 20 and 14 times higher in the cytoplasmand chromatin, respectively. Nicotine-postponed degradationand increased nuclear accumulation of PDGF AA resulted in activationof RNA synthesis and cell proliferation. PDGF BB, which wasnot internalized by cells did not respond to nicotine treatment.The proposed mechanism of nicotine-PDGF AA co-carcinogenesismay involve inhibition of growth factor degradation at the lysosomallevel and an increased chromatin accumulation of the non-degradedPDGF.     

Absence ofHelicobacter pylori in dental plaques inHelicobacter pylori positive dyspeptic patients

To test the validity of reports on detection ofHelicobacter pylori in the mouth, samples were obtained simultaneously from the gastric mucosa and dental plaques for culture in 94 patients examined consecutively by endoscopy. Histological examinations and serological tests were also performed.Helicobacter pylori was not found in the mouth of any of the patients including 52 who had culture-positive gastric biopsies. Thus earlier results could not be confirmed, however, other techniques such as the polymerase chain reaction might give different results.     

Qualitätssicherung in der Therapie chronischen Schmerzes

Ohne Zusammenfassung The online version of the original article can be found at     

Dopamine receptors on human T- and B-lymphocytes

The presence of functional dopamine receptors on differentiated cells of the mammalian immune system is still under discussion. This study has utilized (-)-[³H]sulpride as a ligand to detect the presence of recognition sites of the dopamine D₂ receptor family on human T- and B-lymphocytes. The (-)-[³H]sulpiride binding was of high affinity (K_d 0.9 nM ± 0.2 nM, specific, saturable (B_max 10.2 ± 1.4 fmol/10⁶ cells) and reversible. The pharmacological characterization of the recognition site suggests, similarities mainly with the D₂ and D₄ rather than D₃ subtype of dopamine receptor. Furthermore, dopamine treatment was able to reduce the intracellular cAMP levels of lymphocytes stimulated with forskolin, thus suggesting a potential functional significance of this dopamine receptor in mediating neural-immune interactions.     

Novel pluripotential neural progenitor lines exhibiting rapid controlled differentiation to neurotransmitter receptor‐expressing neurons and glia

The immortalization of progenitor cells from embryonic murine hippocampus using oncogene‐carrying retroviral vectors is described. Use of a vector encoding the oncogene v‐myc results in lines of nestin‐positive progenitor cells. Limited differentiation ensues if the cells are cultured in the presence of dibutyryl cyclic adenosine monophosphate. In contrast, use of a vector in which the extracellular portion of the epidermal growth factor (EGF) receptor is fused to the neu tyrosine kinase generates lines of pluripotential nestin‐positive progenitor cells, which differentiate upon withdrawal of EGF into neurons and glia. Differentiated neurons expressing action potentials and neurotransmitter receptors make up a high proportion of the cells. These cell lines are useful tools to investigate the characteristics of differentiating neurons and glia, as well as to screen neuroactive drugs. This work has been reported in preliminary form as an abstract (1996 Society for Neuroscience Abstract, #606.20, p. 1537).     

Liver metabolic effects of intestinal shock and naloxone treatment in the rat

The liver metabolic response of rats following a standardized intestinal shock, induced by applying a pressure of 120 cm water on the mesenteric vessels for 60 min, was studied. Immediately prior to the release of the pressure on the vessels saline or naloxone was given either as a single injection or as a continuous infusion. After the reperfusion of the intestine no early disturbances in liver metabolism were found as evidenced from the ATP, glucose and lactate levels in liver biopsies taken 15 min following reflow. Within 60 min of reflow reduction of ATP and increases of glucose and lactate levels occurred. There were no major hemodynamic or liver metabolic differences between saline- and naloxone-treated shocked rats. When saline or naloxone was given as a continuous infusion, the changes in liver metabolism were, however, less severe than those observed in the single injection situation pointing toward a non-specific effect of volume replacement rather than a blockade of opioid receptors. Hepatic hypoxia and/or cellular effects of "shock factors" could be mechanisms of pathophysiologic importance for the disturbed liver metabolism in this shock model.     

Indomethacin in canine acute hemorrhagic pancreatitis

The effects of indomethacin administration on hemodynamics were investigated in canine acute hemorrhagic pancreatitis (AHP). Thirteen mongrel dogs were randomly divided into a fluid treatment group, an indomethacin prophylaxis group (IMP), and an indomethacin therapy (IM) group. Indomethacin (5 mg/kg) was administered as a bolus dosage 30 min before the induction of AHP in the IMP group. In the IM group, indomethacin was also given as a bolus (5 mg/kg) in 5 min starting 30 min after the induction of AHP. AHP was induced with a mixture of trypsin and sodium taurocholate infused into the pancreatic duct. Hemodynamics were monitored during the 4.5 h of surveillance time. Heart rate did not change significantly between the groups. Indomethacin prophylaxis maintained mean arterial pressure at a significantly higher level (P less than 0.05) and prevented the initial fall in blood pressure when compared to the fluid treatment or IM group. Indomethacin increased cardiac output (P less than 0.05) in the IM group, but did not differ significantly in the IMP group in comparison with the fluid treatment group. In conclusion, the inhibition of the initial fall in blood pressure by indomethacin in AHP suggests prostaglandins to play a role in hemodynamic changes and pancreatic shock to be "septic" as evaluated by hemodynamic changes.     

The role of hyperthermic perfusion as a first step in the treatment of soft tissue sarcoma of the extremities

Eighty-six patients with locally advanced, high-grade soft tissue sarcomas of the extremities were studied prospectively in order to determine the efficacy of hyperthermic perfusion (HP) or hyperthermic antiblastic perfusion (HAP) as the first step of a combined multimodality therapy. The immediate response was evaluated in terms of tumor regression, and results confirmed the in vivo sensitivity of human sarcomas to the selective antineoplastic action of heat alone or combined with drugs (melphalan, actinomycin D, and cis-platinum). HAP has been shown to be simpler and safer than HP, and it is now currently routinely employed. As far as the long-term cure is concerned, all the patients have been evaluated for functional results, locoregional control, and survival, according to the different treatment schedules. The first clinical trials employed HP or HAP followed by delayed surgery alone. In 11 of 17 evaluable patients treated with HP, and in 17 of 29 treated with HAP, conservative surgery could be performed. A high incidence of locoregional relapse (24%) occurred, with low overall survival rates: 50.1% and 31.7% at 5 and 10 years after HP plus surgery, and 47.9% after HAP plus surgery at both 5 and 10 years. The protocol was, therefore, modified to include continuous intraarterial infusion of Adriamycin® (ADR) (17 patients) or radiotherapy (9 patients) before surgery. The results obtained thus far may be summarized as follows: (a) conservative surgery with functional limb-salvage was possible in all patients; (b) the percentage of locoregional failure decreased to approximately 12% after HAP + ADR infusion + excision, the 5- and 10-year overall survival rates both being 77.6 %, and the 5- and 10-year disease-free rates both being 57.8%; (c) no local recurrences occurred in the group treated with HAP + radiotherapy + excision with a 5-year overall survival rate of 71.5% and a 5-year disease-free rate of 50.4%. In conclusion, the combined multimodality approaches employed appear to have improved both functional results and long-term cure, even though these must be further confirmed on a larger series of patients.

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Resumen Ochenta y seis pacientes con sarcomas de los tejidos blandos de las extremidades, de alto grado histológico, e invasión local avanzada fueron estudiados en forma prospectiva con el objeto de determinar la eficacia de la perfusión hipertérmica (PH) o la perfusión hipertérmica antiblástica (PHA) como primer paso dentro de una terapia combinada multimodal.La respuesta inmediata fue valorada en términos de la regresión tumoral, y los resultados confirmaron la sensibilidad in vivo de los sarcomas humanos a la acción antineoplásica selectiva del calor sólo o combinado con drogas (melfalán, actinomicina D, y cis-platino). La PHA ha demostrado ser más sencilla y más segura que la PH y actualmente es utilizada en forma rutinaria.En lo referente a curación a largo plazo, todos los pacientes han sido evaluados en cuanto a resultados funcionales, control locorregional, y supervivencia, de acuerdo a los diferentes programas terapéuticos.En los primeros ensayos clínicos se utilizó PH o PHA seguida de cirugía solamente. En 11 de 17 pacientes valorables tratados con PH y 17 con PHA, fue posible realizar cirugía conservadora. Se presentó una incidencia alta de relapso locorregional (24%), con tasas bajas de supervivencia global: 50.1% y 31.7% a 5 y 10 años con PH y cirugía, y 47.9% con PHA y cirugía tanto a 5 como a 10 años.El protocolo fue consecuentemente modificado para incluir una infusión intraarterial continua de Adriamicina® (ADR) (17 pacientes) o radioterapia (9 pacientes) antes de la cirugía.Los resultados logrados hasta el momento pueden ser resumidos así: (a) la cirugía conservadora con salvamento del miembro fue posible en la totalidad de los pacientes; (b) el porcentaje de falla locorregional disminuyó aproximadamente 12% después de PHA + infusión de ADR + resección, con supervivencias globales a 5 y 10 años de 77.6%, y tasas de estado libre de enfermedad a 5 y 10 años de 57.8%; (c) no se presentaron recurrencias locales en el grupo tratado con PHA + radioterapia + resección, con una tasa de supervivencia global a 5 años de 71.5% y una tasa de estado libre de enfermedad a 5 años de 50.4%.En conclusión, los aproches con terapia combinada multimodal empleados parecen haber mejorado tanto los resultados funcionales como las tasas de curación a largo plazo, aunque estos resultados aún deben ser reconfirmados en una serie mayor de pacientes.

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Résumé Une étude prospective concernant 86 malades qui présentaient un sarcome des parties molles des membres de stade évolutif avancé a été entreprise pour déterminer l'efficacité de la perfusion hyperthermique ou de la perfusion hyperthermique antiblastique en tant que première étape d'un traitement à modalités multiples.La réponse immédiate a été appréciée en fonction de la régression tumorale. Les résultats ont confirmé la sensibilité in vivo des sarcomes humains à l'action antinéoplasique sélective de la chaleur employée isolemment ou combinée avec des drogues (melphalan, actinomycine D, et cis-platinum). La perfusion hyperthermique antiblastique s'est montrée plus simple et plus sûre que la perfusion hyperthermique, et de ce fait est devenue une méthode thérapeutique normalement employée.Pour apprécier l'action thérapeutique à long terme tous les malades ont été étudiés en tenant compte des résultats fonctionnels, du contrôle loco-régional, et de la survie obtenus selon les différentes thérapeutiques appliquées.Les premiers essais ont eu recours à l'hyperthermie thermique ou à l'hyperthermie thermique antiblastique suivie d'une intervention chirurgicale. Chez 11 des 17 malades traités par l'hyperthermie thermique, et chez 17 des 29 malades soumis à l'hyperthermie antiblastique le traitement chirurgical conservateur a pu être réalisé. Les résultats furent les suivants: fréquence importante des récidives loco-régionales (24%); taux global de survie bas: 50.1% et 31.7% à 5 ans et 10 ans après perfusion hyperthermique suivie de chirurgie, ce taux étant de 47.9% après perfusion hyperthermique antiblastique suivie de chirurgie à 5 ans et 10 ans.En fonction de ces résultats le protocole thérapeutique fut modifié en y ajoutant une transfusion intra-artérielle continue d'Adriamycine® (17 malades) ou de la radiothérapie (9 malades) avant l'intervention.Les résultats obtenus à ce jour peuvent se résumer ainsi: (a) la chirurgie conservatrice permettant de sauver un membre fonctionnel est toujours possible; (b) la poucentage d'échec régional décroit environ jusqu' à 12% après perfusion hyperthermique antiblastique associée à la perfusion d'Adriamycine® et l'excision, le taux global de survie à 5 ans et 10 ans étant de 77.6%, le taux d'absence de la maladie à 5 ans et 10 ans étant de 57.8%; (c) aucune récidive locale n'est survenue dans le groupe traité par perfusion hyperthermique antiblastique associé à la radiothérapie et à l'exérèse, le taux global de survie à 5 ans étant de 71.5% et le taux d'absence de la maladie à 5 ans étant de 50.4%.En conclusion le traitement qui a été employé associant plusieurs modalités thérapeutiques a entrainé une amélioration des résultats fonctionnels et de la cure à long terme encore que ce fait demande a été confirmé par une étude étendue à un plus grand mombre de malades.

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Supported by Special Project Hyperthermia from the Italian Ministry of Health.     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Reversal by ribo- and deoxyribonucleosides of dehydroepiandrosterone-induced inhibition of enzyme altered foci in the liver of rats subjected to the initiation-selection process of experimental carcinogenesis

The effect of dehydroepiandrosterone (DHEA) on the activityof NADPH-producing enzymes and the development of enzyme-alteredfoci has been investigated in the liver of female Wistar ratssubjected to an initiating treatment (a necrogenic dose of diethylnitrosaimine)followed, 15 days later, by a selection treatment [a 15-dayfeeding of a diet containing 0.03% 2-acetylamlnofluorene (2-AAF),with a partial hepatectomy at the midpoint of this feeding].At the end of the selection treatment all rat groups received,for 15 days, a basal diet containing, when indicated, 0.05%phenobarbital (PB) and/or 0.6% DHEA. The effect of DHEA on theactivity of NADPH producing enzymes was also studied in normalrats fed, for 15 days, a diet containing 0.6% DHEA and in theirpair-fed controls. DHEA caused a 43–58% inhibition ofglucose-6-phosphate dehydrogenase (G6PD) and, respectively,338–420% and 21–24% increases in malic enzyme (ME)and isocitric dehydrogenase activities in all rat groups. Thiswas coupled with a great fall in the production of ribulose-5-phosphate,while no change in NADP⁺/NADPH ratio occurred. Hepatocytes,isolated from DHEA-treated rats, exhibited a very low activityof hexose monophosphate shunt (HMS), which was not stimulatedby methylene blue, an exogenous oxidizing agent that markedlystimulated HMS activity in control hepatocytes. DHEA causeda great fall in the percentage of liver occupied by -glutamyltranspeptidase(GGT)-positive foci, in the rats subjected to the initiation- selection treatments. PB enhanced the development of thesefoci, an effect which was completely overcome by DHEA. In addition,focal cells no longer expressed a G6PD activity higher thanthat of surrounding liver in DHEA-treated rats, but exhibiteda high histochemical reaction for ME. DHEA also caused a greatfall in labelling index of GGT-positive foci. Starting at theend of 2-AAF feeding, a mixture of ribonucleosides (RNs) ofadenine, cytosine, guanine and uracil and of deoxyribonucleosides(DRNs) of adenine, cytosine, guanine and thymine were injectedi.p. every 8 h for 12 days to the rats subjected to the initiation- selection treatments plus PB. Rats were killed 3 days afterthe end of RN and DRN treatments. These treatments completelyovercome the DHEA effect on the development of GGT-positivefoci and DNA synthesis by the focal cells, without affectingG6PD activity of both whole liver and putative preneoplasticfoci. Experiments with labeled nucleosides revealed that RNsand DRNs produced derivatives that were incorporated into liverDNA. These data indicate that liver of DHEA-treated rats produceenough NADPH for reduction of RNs to DRNs and growth. The antipromotingeffect of DHEA could depend on a relative deficiency of nudeosidesfor DNA synthesis, caused by a great fall in pentose phosphateproduction.