Herbert A. Neumann

Cytotoxic activity of the thioether phospholipid analogue BM 41.440 in primary human tumor cultures

In the paper Cytotoxic Activity of the Thioether Phospholipid Analogue BM 41.440 in Primary Human Tumor Cultures by Dieter B.J. Herrmann and Herbert A. Neumann, Lipids 22, 955-957 (1987), the formula of BM 41.440 given in Scheme 1 on page 955 is incorrect. The correct formula is shown on page 952. In the paper Phase I Trial of the Thioether Phospholipid Analogue BM 41.440 in Cancer Patients by Dieter B.J. Herrmann, Herbert A. Neumann, Wolfgang E. Berdel, Manfred E. Heim, Michael Fromm, Dietmar Boerner and Uwe Bicker, Lipids 22, 962-966 (1987), the chemical structure of BM 41.440 on page 962 is in error. The substituent in position-2 should be methoxymethyl. The correct structure is shown on page 952.

Gibt es die „Febrile Proteinurie“?

SummaryThe significance of proteinuria during febrile infectious diseases is widely underestimated, although the more marked proteinuria probably signalizes a parainfectious nephropathy rather than a functional disorder. This study shows that mild proteinuria of less than 0.65 g/24 h (normal range less than 0.3 g/24 h using the sensitive tannine-FeCl3-technique) might be caused by the elevated body temperature alone. 9 out of 18 volunteers without renal disease undergoing experimental hyperthermia of 40–41° C for 1–2 h did not develop a proteinuria according to quantitative and qualitative (SDS-PAGE) measurements. In 6/18 the amount and composition of urinary proteins changed giving a glomerular type of proteinuria, possibly caused by temperature related transient glomerular alterations. In 3/18 a mild glomerulopathy existed before hyperthermia, as deduced from a glomerular pattern despite a quantitatively physiological proteinuria, leading in all 3 to pathological proteinuria during hyperthermia. In all 18 volunteers alterations reversed to normal within 12 h.Therefore, the degree of proteinuria during febrile diseases should be considered. Proteinuria of less than 0.5–1 g/24 h in adults might be explained by an altered glomerular function alone. Proteinurias exceeding this value, with a slow regressing tendency will indicate glomerular or tubulo-interstitial diseases, caused possibly by immunologic or toxic products resulting from underlying infectious disease.The significance of proteinuria during febrile infectious diseases is widely underestimated, although the more marked proteinuria probably signalizes a parainfectious nephropathy rather than a functional disorder. This study shows that mild proteinuria of less than 0.65 g/24 h (normal range less than 0.3 g/24 h using the sensitive tannine-FeCl3-technique) might be caused by the elevated body temperature alone. 9 out of 18 volunteers without renal disease undergoing experimental hyperthermia of 40-41 degrees C for 1-2 h did not develop a proteinuria according to quantitative and qualitative (SDS-PAGE) measurements. In 6/18 the amount and composition of urinary proteins changed giving a glomerular type of proteinuria, possibly caused by temperature related transient glomerular alterations. In 3/18 a mild glomerulopathy existed before hyperthermia, as deduced from a glomerular pattern despite a quantitatively physiological proteinuria, leading in all 3 to pathological proteinuria during hyperthermia. In all 18 volunteers alterations reversed to normal within 12 h. Therefore, the degree of proteinuria during febrile diseases should be considered. Proteinuria of less than 0.5-1 g/24 h in adults might be explained by an altered glomerular function alone. Proteinurias exceeding this value, with a slow regressing tendency will indicate glomerular or tubulo-interstitial diseases, caused possibly by immunologic or toxic products resulting from underlying infectious disease.

[Changes in clinical and immunological laboratory parameters of healthy adults after exposure to a one-hour 40 degree C-whole-body hyperthermia (author's transl)].

There are no signs of organ lesions in healthy subjects exposed to an 1-hour 40 degree C whole-body hyperthermia, induced by radiofrequency or infrared light. As to the immunological in vitro parameters, only a slight decrease of the relative T-cell count is seen, T-cell functions however being normal. A leukocytosis appearing during infrared-induced hyperthermia is probably related to the erythema caused by skin heating. About possible indications and clinical values of this treatment, nothing can however be said so far.SummaryThere are no signs of organ lesions in healthy subjects exposed to an 1-hour 40° C whole-body hyperthermia, induced by radiofrequency or infrared light.As to the immunological in vitro parameters, only a slight decrease of the relative T-cell count is seen, T-cell functions however being normal.A leukocytosis appearing during infrared-induced hyperthermia is probably related to the erythema caused by skin heating.About possible indications and clinical values of this treatment, nothing can however be said so far.ZusammenfassungNach einer einstündigen, durch Dezimeterwellen oder Infrarotlicht induzierten Ganzkörperhyperthermie von 40° C, treten bei Gesunden keine Anzeichen für Organschäden auf.Unter den immunologischen in vitro Parametern findet sich lediglich ein leichter Abfall der relativen T-Zell-Konzentration, jedoch ohne Beeinträchtigung der T-Zellfunktionen.Eine Leukozytose die während der Infrarot-induzierten Hyperthermie auftritt, wird auf das Hitze-Erythem zurückgeführt.Über Indikation oder Nutzen einer solchen Behandlungs-Maßnahme kann jedoch noch nichts ausgesagt werden.

Treatment of human clonogenic tumor cells and bone marrow progenitor cells with bleomycin and peplomycin under 40.5°C hyperthermia in vitro

Tumor cells derived from 13 different individual human tumors were plated in a colony forming monolayer assay. The effect of bleomycin and peplomycin on colony formation was assessed in normothermic conditions and after a hyperthermic treatment at 40.5 degrees C for 2 h at the beginning of the culture. In three out of the 13 tumor samples (two colon carcinomas, one malignant melanoma), hyperthermic incubation resulted in a thermal enhancement of the effects of bleomycin and peplomycin. In addition, human bone marrow progenitor cells (CFU-C) were subjected to the same procedure. Peplomycin proved to be less toxic to CFU-C than bleomycin. In samples from eight different donors, homogeneous dose-response curves were observed. There was no difference between normo- and hyperthermic incubation.

Klinisch-chemische Untersuchungen an Tumorpatienten unter Zytostatica- und Ganzkörperhyperthermiebehandlung

14 patients with tumors in generalised stages (Hodgkins disease, oat-cell-carcinoma, Fibrosarcoma, acute leukemia) were treated altogether 54 times with cytostatics in combination with hyperthermia. The temperature was induced by microwaves with a frequency of 27 MHz. A temperature of 40 degrees C was reached after 40 min. At this point cytostatics were applicated; afterwards the temperature was maintained for one hour at 40-40,5 degrees C. Cardia, pulmonary and circulatory complications did not occur. Controls of the laboratory parameters could exclude effects on electrolytes, muscles, blood, liver and kidney. The laboratory controls were made before, during, immediately after and 24 h after hyperthermia. There were no signs for an enhancement of toxicity typical for cytostatics. The observations are compared to the results of other investigators. To date the therapeutic effect of this treatment can not be stated.Summary14 patients with tumors in generalised stages (Hodgkins disease, oat-cell-carcinoma, Fibrosarcoma, acute leukemia) were treated altogether 54 times with cytostatics in combination with hyperthermia. The temperature was induced by microwaves with a frequency of 27 MHz. A temperature of 40° C was reached after 40 min. At this point cytostatics were applicated; afterwards the temperature was maintained for one hour at 40–40,5° C. Cardiac, pulmonary and circulatory complications did not occur. Controls of the laboratory parameters could exclude effects on electrolytes, muscles, blood, liver and kidney. The laboratory controls were made before, during, immediately after and 24 h after hyperthermia. There were no signs for an enhancement of toxicity typical for cytostatics.The observations are compared to the results of other investigators. To date the therapeutic effect of this treatment can not be stated.ZusammenfassungBei 14 Patienten mit Tumoren in generalisierten Stadien (Morbus Hodgkin IV, Kleinzelliges Bronchial-Carcinom, Fibrosarkom, Akute lymphatische Leukämie) wurde insgesamt 54mal die zytostatische Behandlung in Kombination mit Ganzkörperhyperthermie durchgeführt. Die Temperaturerhöhung wurde durch Mikrowellen einer Frequenz von 27 MHz erzeugt. Die gewünschte Temperatur von 40° C wurde nach 40 min erreicht. Zu diesem Zeitpunkt erfolgte die Zytostatikaapplikation; danach wurde die rectal kontrollierte Temperatur von 40–40,5° C noch für 1 h lang aufrechterhalten. Komplikationen von seiten der Lunge, des Herzens und des Kreislaufs traten nicht auf.Durch Kontrolle organspezifischer bzw. funktionsspezifischer Laborparameter konnten Veränderungen an Leber, Niere, Elektrolythaushalt, Muskulatur und Blutzellen ausgeschlossen werden. Die Laborkontrollen erfolgten vor, während, unmittelbar nach und 24 h nach der Hyperthermiebehandlung. Es ergaben sich keine Hinweise auf eine Verstärkung der zytostatika-typischen Toxizität.Die Ergebnisse werden mit den Ergebnissen anderer Gruppen verglichen. Der therapeutische Effekt des kombinierten Vorgehens ist zum derzeitigen Zeitpunkt noch nicht beurteilbar.

Effect of Hyperthermia at 40.5° C and Chemotherapy on Various Human Tumors in Vitro

The possibility of enhancing the effect of cytostatic drugs on tumor cells by means of hyperthermia has been clearly shown by many in vitro and in vivo experiments (Hahn 1982, 1983). In most experiments, experimental cell lines and experimental animal tumors have been used: in only a few have data been obtained using human tumor samples (Mann et al. 1983). With the use of a tumor colony forming assay it is possible to test human tumor samples for their individual drug sensitivity and the possible influence of hyperthermia.

Predicting the Sensitivity of Human Cancers to Combined Chemotherapy and Hyperthermia

In order to estimate its ability to predict the thermochemosensitivity of human cancers, a rapid in vitro assay based on morphological changes in the nucleus was performed on eight different human tumors (four malignant melanomas, two lung tumors, one renal carcinoma, and leukemia K-562). Nude mice, implanted with tumors, supplied the tumor material, with the exception of leukemia. Nimustine, melphalan, mitomycin C, vincristine and vinblastine were tested. Tumor cells developed karyorrhectic changes after incubation for 4 h with each of the aforementioned five drugs. An increase in the karyorrhectic changes was observed with hyperthermia at 43 degrees C. The individual tumors showed different sensitivities to 43 degrees C. Five of the eight tumors were significantly sensitive to 43 degrees C. However, in two thermosensitive tumors no drug enhancement was recognized at 43 degrees C. In four tumors several drugs were synergistically enhanced by hyperthermia at 43 degrees C. This study suggests that this simple method may be of clinical use in predicting response to thermochemotherapy.

A Rapid in Vitro Assay for Predicting Thermochemosensitivity of Human Cancer: Comparison with Clonogenic Assay

We previously reported a rapid in vitro assay based on morphological changes in the nucleus in order to predict response to thermochemotherapy. It was strongly suggested that this simple method may be clinically useful. In the present study, a comparison with the clonogenic assay was carried out on eight different human tumors (three malignant melanomas, two lung carcinomas, two colon carcinomas and one leukemia). Melphalan, mitomycin C and vincristine were tested. Correlation between the two test systems was dependent upon the criteria for each test system. At the level of less than 50% survival of colony as compared with normothermic dishes in clonogenic assay, there was a high correlation between the two test systems for sensitive tumor to 43 degrees C. In respect of response to thermochemotherapy, when only karyorrhexis changes in the nucleus were selected as an activity criteria in our cytotoxic test, parallel data between the two test systems were obtained.