Inhibition of gluconeogenesis and <Emphasis Type="Italic">p</Emphasis>-aminohipuric acid accumulation in rat renal cortical slices by ionic and nonionic contrast media

Background. Renal dysfunction is a well-recognized complication induced by contrast media (CM). Nonionic CM have been introduced into clinical use to replace conventional ionic CM in an effort to reduce toxicity. However, the nephrotoxic effects of nonionic CM have not been fully evaluated. We previously determined the activities of N-acetyl--d-glucosaminidase and -glutamyltransferase released from rat and human renal slices incubated with contrast media. Dose-dependent enzyme release from renal slices was observed, but there was no statistical difference in the increase of enzyme activities between ionic and nonionic CM. The present experiment was conducted to compare the effects of ionic and nonionic CM on the metabolic function of rat renal slices.Methods. Rat renal cortical slices were incubated with ionic CM (diatrizoate, iothalamate) and nonionic CM (iopamidol, iohexol) at 37°C for 90min. To examine the dose–response effects of CM on gluconeogenesis and p-aminohipuric acid (PAH) accumulation in the rat renal slices, slices were incubated with 30, 60, and 90mgI/ml of CM. The inhibitory effects of nonionic CM on gluconeogenesis and PAH accumulation were compared with those of ionic CM in an independent experiment, in which slices were incubated with CM at a concentration of 60mgI/ml. In addition, rat renal slices were incubated with mannitol instead of CM to investigate the effects of osmotic pressure on gluconeogenesis and PAH accumulation.Results. A dose-dependent reduction of gluconeogenesis in rat renal slices was demonstrated by both ionic CM and nonionic CM. The inhibition of PAH accumulation was dose-dependent with nonionic CM, but not with ionic CM. Gluconeogenesis and PAH accumulation within the renal slices were both inhibited according to the increase in osmotic pressure produced by mannitol. The reduction in gluconeogenesis and PAH accumulation within the rat renal slices incubated with 60mgI/ml of nonionic CM were significantly less than those resulting from the same concentration of ionic CM.Conclusions. Nonionic CM is less nephrotoxic than ionic CM with regard to gluconeogenesis and PAH accumulation in rat renal slices. These differences in nephrotoxic effect between ionic and nonionic CM may in part be attributable to differences in osmotic pressure.     

Experimental study of renal disorder caused by oxaliplatin in rat renal cortical slices

Background Oxaliplatin is a newly developed antitumor platinum complex that is known to have low nephrotoxicity. The inhibitory effects of oxaliplatin on several tubular functions were compared with those of cisplatin and carboplatin, using a renal cortical slice system.Methods and results Rat renal cortical slices were incubated with 0.25mM to 2.0mM of oxaliplatin, cisplatin, on carboplatin at 37°C for 120min. Para-amino hippuric acid (PAH) accumulation, gluconeogenesis, and ATP content in the rat renal slices were determined. PAH accumulation was not inhibited by carboplatin, but it was signific-antly inhibited by oxaliplatin and cisplatin. Inhibition of PAH accumulation by cisplatin was greater than that by oxaliplatin. Gluconeogenesis was not decreased by carboplatin, but it was suppressed by oxaliplatin and cisplatin in a dose-dependent manner. The decrease in gluconeogenesis induced by oxaliplatin was significantly greater than that induced by cisplatin. ATP content in the renal slices was decreased by oxaliplatin, cisplatin, and carboplatin to almost the same extent. As an in vivo experiment, 21.6mmole/kg of oxaliplatin, cisplatin, or carboplatin was injected into rats; then blood urea nitrogen (BUN) and serum creatinine were determined on day 4. Significantly elevated levels of BUN and serum creatinine were observed only in the rats injected with cisplatin.Conclusions Oxaliplatin did not cause nephrotoxicity in the in vivo study; however, the nephrotoxic pattern of oxaliplatin observed in the renal cortical-slice system resembled that of cisplatin. The reason why oxaliplatin is less nephrotoxic than cisplatin in vivo could not be fully elucidated in the present experiment using the renal cortical-slice system.     

173. Tierexperimentelle Ergebnisse mit einem voll implantierbaren Distraktionsgerät zur operativen Beinverlängerung

Zusammenfassung Zur operativen Beinverlängerung wurde ein neues Femur-Distraktionsgerät entwickelt. Das Gerät besteht aus einem elektronisch programmierbaren Distraktionsaggregat einschließlich Kraftquelle und einer zweiteiligen Führungsschiene. Das Gesamtsystem ist voll versenkbar und schafft Übungsstabilität während der Distraktionsphase. Die Funktionen Vorlauf — Stop —Rücklauf können transcutan induktiv gesteuert werden. Ein für das Tierexperiment speziell entwickelter Prototyp des Gerätes wurde an Schafen erfolgreich erprobt.     

Vertical lengthening of the unilateral cleft lip after a triangular flap repair

Summary A triangular flap repair for unilateral cleft lip is stated to have the potential problem of creating a lip that is too long. Although preoperative measurements were performed with calipers, the gap created in the medial segment was directly measured during the procedure, in order to determine the size of the flap more precisely. Ninety patients with complete unilateral cleft lips underwent a triangular flap repair using this method. The symmetry of the Cupid's bow was evaluated at a follow-up period averaging between six years and three months. Sixty-two lips obtained symmetry and the remaining 28 cases showed a lip which was too long; none of the lips were too short. The comparison between 27 primary palate clefts (UCLA) and 63 primary and secondary palate clefts (UCLP) showed no significant difference in the surgical result. The preoperative shortness of the lip on the cleft side was significantly greater in the too long group (5.01 ± 0.95 mm) than in the symmetry group (4.40 ± 0.87 mm). The width of the flap used was significantly larger in the too long group (3.76 ± 0.79 mm) than in the symmetry group (3.42 ± 0.69 mm). The triangular flap repair with intraoperative measurements is considered to be beneficial, although preoperative measurements provide an optimal design in most cases. It is suggested that the use of a wider triangular flap results in a lip which tends to be too long in spite of the preoperative shortness on the cleft side.     

Case Report: Intracerebral Hemorrhage After γ-Knife Surgery for Metastatic Brain Tumor

The authors report a case of a 69-year-old man with metastatic brain tumors who died of spontaneous intracerebral hemorrhage 3 days after -knife surgery. He had been suffering from lung cancer with multiple systemic metastasis. Preoperative magnetic resonance images showed two well-defined round lesions with intratumoral hemorrhage in the left frontal and right occipital lobe. There was no bleeding tendency in the hematological examination and the patient was normotensive. -Knife surgery was performed on both lesions in a single session. However, the patient died of massive intracerebral hemorrhage from the left frontal lesion 3 days after the surgery. There have been no previous reports of mortality resulting from spontaneous intracerebral hemorrhage after -knife surgery in metastatic brain tumors documented in the literature. It is likely that the two events, -knife surgery and spontaneous intracerebral hemorrhage, occurred separately and were not associated. However, it is worth noting that there is a possibility of bleeding after -knife surgery, especially in a metastatic brain tumor with preexisting intratumoral hemorrhage as in our case.     

Secretory territories and rate of matrix production of osteoblasts

The secretory territories of rat osteoblasts on the parietal bone were measured directly using scanning electron microscopy. The mean territory of 4620 cells in 19 fields was 154 m² per osteoblast. The range for the fields was 136 to 177 m² per osteoblast. Four hundred cells were measured individually—for these the mean value per osteoblast was 143 m² with a standard deviation of 33. The daily rate of apposition over an 8 day period was 3.12 m (standard deviation 0.22) measured by tetracycline marking of the mineral front. This gave a daily matrix production rate of approximately 470 m³ per osteoblast.

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Zusammenfassung Die Ausscheidungsbereiche von Ratten-Osteoblasten des Scheitelbeines wurden mit dem Raster-Elektronenmikroskop direkt gemessen. Der durchschnittliche Bereich von 4620 Zellen in 19 Gesichtsfeldern war 154 m² per osteoblast. Der Streubereich lag in den verschiedenen Gesichtsfeldern zwischen 136 und 177 m² per Osteoblast. 400 Zellen wurden einzeln gemessen. Bei diesen war der Durchschnittswert per Osteoblast 143 m², mit einer Standard-Abweichung von 33. Die tägliche Anlagerungsrate während einer Periode von 8 Tagen war 3,12 m (Standard-Abweichung 0,22); sie wurde mittels Tetracyclinmarkierung der Mineralisierungsfront gemessen. Dies ergab eine tägliche Produktionsrate der Matrix von etwa 470 m³ per Osteoblast.

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Résumé Les territoires sécrétoires des ostéoblastes d'os pariétal de rats sont déterminées en utilisant la microscopie électronique à balayage. Le territoire moyen de 4.620 cellules, dans 19 territoires, est de 154 m² par ostéoblaste. Les valeurs extrêmes par champ varient de 136 à 177 m² par ostéoblaste. Quatre cent cellules sont mesurées individuellement; la valeur moyenne par ostéoblaste est de 143 m³ avec une déviation standard de 33. Le taux d'apposition journalier, mesuré par la tétracycline pendant 8 jours, est de 3.12 m (déviation standard 0.22). Ce qui correspond à une production matricielle journalière d'environ 470 m³ par ostéoblaste.

     

Immunologic tolerance in renal transplantation

Summary The current excellent short-term results of renal transplantation are achieved at the expense of complications of chronic immunosuppression. These include increased risk for infection, malignancy, and long-term deterioration of function (chronic allograft nephropathy). The induction of transplantation tolerance, the long-term acceptance of an allograft without continuous immunosuppression, has been a goal of transplant immunologists for the last 40 years. Unfortunately, this has been easier to achieve in rodents than in humans. Nevertheless, this body of research has significantly increased our knowledge of the workings of the immune system and, specifically, how the body differentiates between self and nonself. Using these insights, several promising approaches to the clinical induction of transplant tolerance have emerged and are undergoing clinical evaluation.     

Taxol inhibits osteoclastic bone resorption

Summary We have examined the effect of the anti-tumor compound taxol, on osteoclastic bone resorption. In the bone slice assay, taxol (0.1–0.001 M) dose-dependently inhibited bone resorption with an IC₅₀ of 0.08 M. Osteoclast survival on bone slices was unaffected by 0.01–1 M taxol, but 10 M was cytotoxic. Taxol (1 M) also ihibited osteoclast spreading (45%) on fibronectin-coated slides. The antiproliterative effects of taxol are due to its unique ability to stabilize microtubules. Primary osteoclasts are nonproliferating end cells, so taxol probably inhibits bone resorption by intertering with other microtubule-dependent functions such as cell polarization, motility or vesicle exocytosis. Since these inhibitory effects on osteoclasts in vitro are seen with therapeutically relevant concentrations, taxol therapy may have beneficial side-effects e.g. inhibition of hyperealcemia and bone metastases.     

Differential expression of transforming growth factor-β1 and β3 as well as C-FOS mRNA in normal human prostate,benign prostatic hyperplasia and prostatic cancer

Summary The discrepancy between the incidence of latent prostate cancer and that of clinically overt carcinoma suggests that there can be different courses in the biological progression of prostate cancer. As this cancer is detected increasingly at an infraclinical stage, markers are needed to indicate which lesions will progress and lead to the patient's death. To investigate the possibility that specific growth factors and/or proto-oncogenes are expressed differentially, we measured mRNA levels of transforming growth factors 1 (TGF-1), TGF-2 and TGF-3 and of the c-fos and c-jun oncogenes by Northern blotting in normal prostate, benign prostatic hyperplasia (BPH) and prostate cancer. Our data demonstrate that expression of TGF-1 increased, whereas that of TGF-3 fell to an almost undetectable level in carcinoma. Expression of c-fos followed the TGF-1 pattern, whereas no difference could be seen in c-jun expression in cancer as compared with BPH and normal prostate. The differential expression of TGF-1, TGF-3 and c-fos could possibly be used to improve the characterisation of prostate cancer. Long-term follow-up of patients may indicate whether mRNA levels of these growth factors and oncogenes correlate clinically and whether they can be used as markers for progression in human prostate cancer.     

Tierexperimentelle Untersuchungen über die Wundheilung unter dem Einfluß von Phenothiazinderivaten

Zusammenfassung Zur Klärung der Frage, ob der Künstliche Winterschlaf in irgendeiner Form Wundheilungsvorgänge beeinflußt, wird die primäre und sekundäre Wundheilung am Meerschweinchen untersucht, die durch Gagen von täglich je 10 mg N-(2-Dimethylaminopropyl)-Phenothiazin (A) und N-(3-Dimethylaminopropyl)-3chlor-Phenothiazin (M) und 20 mg Methylphenylpiperidincarbonyläthylhydrochlorid (D) je Kilogramm bis zu 6 Tagen in den sog. künstlichen Winterschlaf versetzt werden. Die Tiere werden 2,4 und 6 Tage nach den Eingriffen getötet. Das Wundgebiet wird histologisch untersucht und das Ergebnis mit dem an Kontrolltieren gewonnenen verglichen.Die Versuche zeigen, daß in den genannten Zeiträumen bei den Winterschlaftieren gegenüber den Kontrolltieren keinerlei Unterschiede in der Wundheilung auftreten.Während die histologische Untersuchung der Nieren keinen pathologischen Befund ergibt, zeigt der histologische Befund der Leber bei einer großen Zahl der Winterschlaftiere kleinfleckige Massennekrosen im SinneRössles, die bei keinem der Kontrolltiere zu finden sind und deren Genese erörtert wird.     

Expression of transforming growth factor β in renal cell carcinoma and matched non-involved renal tissue

TGF1 is one of several cytokines produced by proximal tubular and renal cancer cells. Previous studies have been mainly focused on determining plasma or serum TGF levels, its effect on RCC cultures, and the expression of TGF mRNA. Cancerous and autologous normal kidney samples were obtained from 24 patients treated by radical nephrectomy. TGF1 expression was determined using a semi quantitative Western blot analysis and immunohistochemistry. Blot densities and immunohistochemical expression intensities in normal and neoplastic tissue were compared, and subsequently correlated to tumor stage, histological type and nuclear grade. All tissue samples examined expressed TGF1; mean tumor to non-involved kidney spot density ratio correlated with advancing stage and higher nuclear grade. The overexpression of TGF1 in certain RCCs may partially explain their resistance to the growth suppression action of TGF. The correlation with tumor stage and grade indicates a possible role in the development of metastatic potential as well as in hosts immune response modulation.     

Use of a pericardial fat pad flap for preventing bronchopleural fistula: An experimental study focusing on the angiogenesis and cytokine production of the fat pad

An experimental study was conducted to determine whether pericardial fat tissue could induce neovascularization and produce cytokines related to tissue repair. Neovascularization was examined using chick chorioallantoic membranes. Pieces of pericardial fat tissue, omentum, and intercostal muscle were individually placed on a number of chorioallantoic membranes and neovascularization induced by each material was assayed 6 days after the implantation. The intensity of neovascularization was in the order of pericardial fat omentum > muscle. Cytokines, such as interleukin 1 (IL-1) and , tumor necrosis factor- (TNF), interferon- (IFN-), and interleukin 6 (IL-6) were assayed in a culture supernatant of pericardial fat tissue. The latter was obtained 24h after the addition of lipopolysaccharide (LPS) following various incubation times. All cytokines other than IFN are known to play a part in tissue repair, whereas IFN is negatively related to tissue repair because it inhibits fibroblast growth. The pericardial fat tissue incubated with LPS produced a certain amount of IL-1 on day 1, and TNF on days 1 and 8, whereafter these values decreased to an undetectable level. Irrespective of the addition of LPS, a large amount of IL-6 was observed in the supernatant of pericardial fat tissue and it was detectable until day 29. On the contrary, INF was not detected at any assay time. These observations suggest that a pericardial fat pad flap could possibly be beneficial in the prevention of bronchopleural fistula after pulmonary resection.     

In-vivo and ex-vivo renal preservation

Summary A new renal perfusate of modified intracellular electrolyte composition made hyperosmolar with mannitol and requiring no additional additives was successfully used to preserve canine kidneys ex-vivo for 48 hours by initial perfusion and hypothermic storage. The new perfusate was also successful in protecting totally ischemic canine kidneys from the lethal effect of two-hours of normothermic exposure in-vivo. — The preservation technique is uncomplicated, the materials involved are inexpensive, and the preservation apparatus is readily transportable.Supported by the Max Kade Foundation, New York, New York.     

The N-Methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) suppresses enfturane-induced opisthotonus in mice

We determined whether enflurane-induced opisthotonus in ddN mice is mediated by N-methyl-D-aspartate (NMDA) receptor using NMDA receptor antagonists dizocilpine (MK-801) and ketamine. Animals were given intraperitoneal injections of 0.2ml saline (control), 2.5 or 5.0mg·kg^–1 dizocilpine in saline, or 20 or 40mg·kg^–1 ketamine is saline 20min prior to exposure to 2.0% enflurane. Incidence of opisthotonus measured during exposure to enflurane for 20min was 49% (n = 51) in saline (control) group, 6.7 (P 0.01 vs control, n = 30) and 15.0% (P 0.01, n = 40) in 2.5 and 5.0mg·kg^–1 dizocilpine group, respectively, and 43.9 (NS, n = 41) and 40.0% (NS, n = 40) in 20 and 40mg·kg^–1 ketamine group, respectively. These results strongly suggest that enflurane-induced opisthotonus is mediated by NMDA receptor. Ketamine failed to suppress significantly due to possibly small dosages. Further, dizocilpine itself produced severe seizures during preenflurane period (30.0 and 40.0% in 2.5 and 5.0mg·kg^–1, respectively), which may be a novel finding.(Komatsu H, Nogaya J, Anabuki D, et al.: The N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) suppresses enflurane-induced opisthotonus in mice. J Anesth 7: 519–522, 1993)     

“High spinal” dysrhaphism

Summary High spinal (cervical and upper thoracic) dysrhaphism usually involves either a meningocele or a dermal sinus tract. These high spinal lesions can have a complex intradural anatomy at the level of the lesion (as this case reports) and are associated with an increased incidence of lower spinal occult dysrhaphic anomalies. It is therefore recommended that patients with high spinal dysrhaphism undergo radiological evaluation of the entire spine to identify those patients with intradural anomalies, define the anatomy for surgery, and investigate the lower spine for associated occult anomalies.     

Transforming growth factor-beta localization during mouse prostate morphogenesis and in prostatic growth abnormalities

Summary Growth and morphogenesis of the prostate involves mesenchymal-epithelial interactions. Transforming growth factor-beta 1 (TGF-1) is one growth factor that may play a role in these paracrine interactions. We have localized TGF-1 by molecular and immunohistochemical analysis in the developing mouse prostate. Accumulations of TGF-1 protein were localized in the mesenchyme surrounding ductules in fetal and neonatal prostate. Previous studies in the mouse prostate reconstitution (MPR) model system have localized accumulations of TGF-1 to regions of oncogene-induced abnormalities. In surgically excised adult human prostate tissues, localized accumulations of TGF-1 are associated with prostate cancer and benign prostatic hyperplasia (BPH). Intracellular TGF-1 was more often associated with stromal cells in BPH and with neoplastic epithelial cells in prostate cancer. The production and accumulation of TGF-1 appears to involve interactions between mesenchymal and epithelial cells. Further experimental studies may clarify the relationships between TGF-1 and abnormal prostatic growth.     

Comparison of adrenoceptor subtype expression in porcine and human bladder and prostate

We have quantified and characterized ₁-, ₂-and -adrenoceptor subtypes in porcine bladder detrusor and bladder neck, human bladder detrusor, and porcine and human prostate. ₁-, ₂- and -adrenoceptor were identified in radioligand binding studies using [³H]prazosin, [³H]RX 821002 and [¹²⁵I]iodocyanopindolol, respectively, as the radioligands. In porcine male and female detrusor and bladder neck and male prostate, adrenoceptors were detected in the order of abundance > _{2 1} (not detectable), with no major differences between the sexes or between detrusor and bladder neck. In human detrusor and prostate the order of abundance was > _{2 1} (not detectable) and ₁ > ₂. respectively. The ₂-adrenoceptors in all tissues were homogeneously of the _2A-subtype as evidenced by competition binding studies with yohimbine, prazosin, ARC 239 and oxymetazoline. The -adrenoceptors represented a mixed population with a dominance of the ₂-subtype in all tissues as demonstrated by competition binding with ICI 118,551 and CGP 20,712A. We conclude that pigs may be a suitable model for studies of detrusor function with respect to adrenoceptor expression. They may be less suitable for studies of bladder neck or prostate function.     

Renal tissue gas tensions during hemorrhagic shock

To evaluate the development of renal hypoxia during hemorrhagic shock, fourteen dogs were induced in this study. The animals were divided equally into a group in which mean arterial pressure (MAP) was kept at 50mmHg (group 1), and into another where MAP was kept at 40mmHg for 180mim (group 2). Renal tissue gas tensions were determined by a mass spectrometer. In the 50-mmHg group, renal tissue oxygen tension (Pr_{O 2}) dropped for 15min following hemorrhage, remained constant for 90min, then fell further for 150min before a plateau was established. In the 40-mmHg group, the Pr_{O 2} dropped for 90min before reaching a plateau. The second Pr_{O 2} decline occurred at the same level in both the 50-mmHg group and the 40-mmHg group. The point at which the same Pr_{O 2} level occurred for each group suggests the cessation of oxygen consumption and the conditions of renal hypoxia. It is assumed that renal hypoxia occurs in 120min at a MAP of 50-mmHg and in 60min at a MAP of 40mmHg.(Murakawa K, Izumi R, Kobayashi A: Renal tissue gas tentions during hemorrhagic shock. J Anesth 3: 10–15, 1989)     

55. Organisationsfragen in der Intensivmedizin

Zusammenfassung Der Begriff Intensivmedizin gliedert sich in die Intensivüberwachung und die Intensivbehandlung. In der klinischen Praxis gehen zwar beide Bereiche oft ineinander über, trotzdem sind sie wegen der unterschiedlichen Anforderungen begrifflich klar voneinander zu trennen. Der Gesamtbettenbedarf für die Intensivmedizin beträgt in der allgemeinen Chirurgie 7–10%, für die Intensivbehandlung im engeren Sinne 3–5%. Die Besetzung mit Pflegepersonal richtet sich in der Intensivüberwachung nach einem Personal: Bettenschlüssel von 1:1, in der Intensivbehandlung von 2:1. Für die Intensivüberwachung wird 1 Arzt auf 3 Betten, für die -behandlung neben dem ärztlichen Leiter der Betteneinheit 1 Arzt auf 2 Betten benötigt. Aus organisatorischen Gründen besitzen die Intensiveinheiten der meisten Krankenhäuser interdisziplinären Charakter. Das bedingt neue Formen ärztlicher Zusammenarbeit; aus dem konsiliarisch zugezogenen Arzt wird der mitbehandelnde Arzt, der für seinen Teil der Therapie die volle Verantwortung übernimmt. Trotzdem muß die ärztlich-organisatorische Leitung der Betten-einheit in einer Hand liegen. Die Befugnisse dieses ärztlichen Leiters berühren aber nicht die Fachkompetenzen der anderen beteiligten Ärzte.

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Organizational problems of intensive care

Summary The term Intensive Care includes both Intensive Observation and Intensive Therapy.In clinical practice, however, those two terms are not distinctly defined although they must be clearly separated because of their different characteristics.The number of beds required for Intensive Care amounts to 7 to 10% for general surgery, whereas 3 to 5% are needed for Intensive Therapy. The ratio of nurses to beds is 1 to 1 for Intensive Observation and 2 to 1 for Intensive Therapy. For Intensive Observation one doctor is needed for 3 beds while for Intensive Therapy one doctor is needed for 2 beds each in addition to a head physician in charge of the Intensive Care ward. For organizational reasons the Intensive Care wards of most hospitals are inter-departmental. This calls for new forms of cooperation among doctors; the consulting doctor is also a doctor in charge who shall be fully responsible for his part in the therapy. Nevertheless, the medical and organizational administration of the Intensive Care ward must be in the hands of one person whose competences, however, do not coincide with the expert competences of the other doctorsin charge.

     

Cytotoxic effect of diphtheria toxin used alone or in combination with other agents on human renal cell carcinoma cell lines

Treatment of renal cell carcinoma (RCC) by conventional chemotherapy and immunotherapy has resulted in minimal remissions. Alternative forms of therapy are therefore being sought. The present study investigated the sensitivity of RCC cell lines to several toxins used alone and in combination with other agents. RCC lines were relatively sensitive to the direct cytotoxic effect of diphtheria toxin (DTX), Pseudomonas aeruginosa exotosin A (PEA) and ricin. Furthermore, DTX in combination with tumor necrosis factor- (TNF-) resulted in synergistic cytotoxic activity. The mechanism of synergy was examined. A possible mechanism of resistance to TNF- in tumor cells is the expression of TNF- mRNA or protein. R11 cells did not constitutively express mRNA for TNF-, however, treatment of R11 cells with TNF- induced the expression of TNF- mRNA. When DTX was used in combination with TNF-, the level of TNF- mRNA induced by TNF- was markedly reduced. These studies suggest that DTX in combination with TNF- can overcome the resistance of RCC lines and that the marked downregulation of TNF- mRNA by DTX may play a role in the enhanced cytotoxicity seen with the combination of DTX and TNF-. Furthermore, the combination treatment might also potentiate the antitumor host responses. The implications of these findings in clinical therapy are discussed.