G.A. Nagel

Aminoglutethimide in the treatment of premenopausal patients with metastatic breast cancer

Eighteen premenopausal patients with progressive metastatic breast cancer were treated with aminoglutethimide (AG)/cortisone. All patients received 1000 mg AG per day in combination with 2 X 25 mg cortisone acetate. Complete (CR) and partial remissions (PR) were achieved in 27.8%, a no change (NC) in 16.7% and progressive disease (PD) in 55.5% of all cases. The clinical results show that AG/cortisone acetate is effective in the therapy of premenopausal as well as postmenopausal patients with metastatic breast cancer. One hormone receptor negative tumour completely responded. Contrary to postmenopausal patients whose low oestradiol levels continuously decrease, oestradiol levels in premenopausal patients were not influenced by treatment. A distinct suppression of the ovarian activity does not occur. Thus concluding, a mechanism--at least partially different from those in the postmenopause and not necessarily of endocrine nature--must exist in the premenopause. We, therefore, no longer think it justified to assert that the therapeutic effect of AG is merely based on medical adrenalectomy.

A CD66a-specific, activation-dependent epitope detected by recombinant human single chain fragments (scFvs) on CHO transfectants and activated granulocytes.

Antibodies to CD66 recognize at least five members (CD66a–e) of the carcinoembryonic antigen (CEA) family. Recombinant human single‐chain Fv fragments (scFvs) that bind specifically to CD66a (biliary glycoprotein) were obtained from a naive human scFv library. The scFvs bound to the N‐domain of CD66a on Chinese hamster ovary (CHO) transfectants but did not bind to freshly isolated peripheral granulocytes or to dimethylsulfoxide‐treated HL‐60 cells. In contrast, scFvs bound well to granulocytes that were short‐term activated with N‐formyl‐Met‐Leu‐Phe or phorbol 12‐myristate 13‐acetate and to human HL‐60 cells that were treated with all‐trans‐retinoic acid to induce granulocytic differentiation. Quantification of antigenic sites showed that the activation‐dependent CD66a epitopes were expressed on nearly all of the CD66a molecules on CHO‐biliary glycoprotein transfectants, but they were detected only on a portion of the molecules on activated polymorphonuclear neutrophils and differentiated HL‐60 cells. Binding of CD66a scFvs to their neoepitopes on prestimulated PMNs induced respiratory burst, suggesting that CD66a is capable of delivering transmembrane signals in these cells.

Erniedrigte Plasmazinkspiegel beim metastasierten Mammakarzinom

Zinc is an essential component of many metalloenzymes for DNA and proteinsynthesis including RNA and DNA polymerases. It has been shown by several investigators that zinc is accumulated in breast cancer tissues. To investigate a possible relation between plasma zinc levels and tumor load, plasma zinc levels were evaluated in 76 patients with non metastatic breast cancer (no evidence for disease after mastectomy) and in 66 patients with metastatic breast cancer. Zinc concentrations were measured in plasma using an atomic absorption spectrophotometer (normal range 80-150 mcg/dl). In patients with metastatic disease plasma zinc concentrations were in the lower region of the normal range or depressed (arithmetic mean: 84.9 SD 21.6 mcg/dl), whereas patients with non metastatic breast cancer had normal zinc levels (arithmetic mean: 126.0 SD 27.7 mcg/dl). The difference between the two groups was highly significant (p = 0.001, t = -9.742, 140 degrees of freedom). It is concluded, that plasma zinc in breast cancer patients is depressed according to the stage of the disease. Based on experimental data a substitution of zinc cannot be recommended.

Vergleichende Untersuchungen zum Prolaktin-, Östrogen-, Gestagen und Androgenrezeptorgehalt menschlicher Mammakarzinome

Ein Rezeptor, der die laktogenen Hormone Prolaktin (mehrerer Spezies) und humanes Wachstumshormon spezifisch, reversibel und mit hoher Affinitat (Kd = 0,23 × 10-10M) bindet, wird in Lebermem-branfraktionen der weiblichen, adulten Ratte nachgewiesen und cha-rakterisiert. Die spezifische Prolaktinbindung ist saturierbar und betragt bei weiblichen Tieren 45 fmol/mg Protein, wahrend sie bei mannlichen und unreifen Tieren fehlt. Mit diesem Assay wird der Prolaktinrezeptorgehalt im Primartumor von 25 Mammakarzinom-patientinnen gemessen. Es findet sich eine spezifische und reversible Prolaktinbindung, die je nach Gewebe von 2 bis 29 % der eingesetzten Totalaktivitat reicht. Mammakarzinome mit dem hochsten Prolaktinrezeptorgehalt weisen die niedrigsten Ostrogen-, Progesteron- und Androgenrezeptorkonzentrationen auf, eine signifikante Beziehung zwischen absolutem Steroidrezeptorgehalt und spezifischer Prolaktinbindung besteht jedoch nicht. Es wird gefolgert, das die Expression von Steroid- und Prolaktinrezeptoren im menschlichen Mammakarzinom unabhangig voneinander erfolgt und auch bei steroidrezeptor-negativen Tumoren moglich ist.

Pathophysiologie der Hyperprolaktinämie beim Mammakarzinom

Bei 514 Mammakarzinompatientinnen wurden im Verlauf der Erkrankung wiederholt die Plasmaprolaktinbasalspiegel bestimmt. Hyper-prolaktinamische Patientinnen wurden einem Prolaktinstimulations-und -inhibitionstest unterzogen und Hormonprofile uber 24 h erstellt. Mittels in vitro kultivierter Hypophysenzellen wurde untersucht, ob in Mammakarzinomgeweben und Seren hyperprolaktinamischer Mammakarzinompatientinnen eine prolaktinfreisetzende Aktivitat nachweisbar ist. 44% der Mammakarzinompatientinnen entwickelten im Verlauf der Erkrankung eine Hyperprolaktinamie. Erhohte Prolaktin-spiegel konnten zu 35 % auf nicht unmittelbar tumorbedingte Einflusse, wie prolaktinstimulierende Pharmaka, operative Eingriffe, Nieren-insuffizienz oder Prolaktinome zuruckgefuhrt werden. Es wird erst-mals auf eine uber 4 Wochen persistierende Hyperprolaktinamie nach Mastektomie hingewiesen. Hyperprolaktinamien, die nicht mit derartigen Einflussen assoziiert waren, waren nur bei Patientinnen mit progredienten, metastasierten Mammakarzinomen nachweisbar. Bei diesen Patientinnen korrelierte die Hohe der Prolaktinspiegel mit Tumorstadium, Zahl der befallenen Organsysteme und Tumoraktivitat, jedoch nicht mit Prognosefaktoren, Blutsenkung oder CEA-Wert. Die Hyperprolaktinamie war nicht paraneoplastisch bedingt. Eine prolaktinfreisetzende Aktivitat in Mammakarzinomgeweben, Seren hyperprolaktinamischer Patientinnen und in konditionierten Medien von verschiedenen Mammakarzinomzellinien konnte als Ursache der mammakarzinomassoziierten Hyperprolaktinamie ausgeschlossen werden.

Medroxyprogesteronacetat in hoher Dosierung beim metastasierenden Mammakarzinom

Im Rahmen der Therapie des metastasierenden Mammakarzinoms wurde MAP in verschiedenen Applikationsformen und Dosierungen eingesetzt. Dabei wurden pharmakokinetische und pharmakodynamische Untersuchung

Structure, Function and Expression of the CEA Gene Family: Diagnostic and Therapeutic Implications

During the search for biochemical differences between tumorous and corresponding normal tissues a quarter of a century ago, the carcinoembryonic antigen (CEA) was found in colonic tumors, but not in normal colonic mucosa (Gold and Freedman 1965; von Kleist and Burtin 1966). With the development of more sensitive analytical methods, CEA and most other “tumor-specific” markers were also detected in normal tissues or in sera of individuals without tumors (for review see Shively and Beatty 1985). Despite this fact, CEA is widely used for the monitoring of tumor patients for recurrence of malignant disease after surgery (Fantini and DeCosse 1990). A continuous rise in the CEA concentration in serum, detected by serial determinations, is an indicator of tumor regrowth or metastasis in patients with adenocarcinomas of the colon, rectum, breast, lung and pancreas. Since an increase of the CEA concentration is often observed before other clinical symptoms are obvious, early therapeutic measures can be taken (e.g., “second-look” surgery in patients with colorectal tumors (Fantini and DeCosse 1990)). However, the diagnostic value of CEA, e.g., for early detection of primary tumors by routine screening, is limited due to the low sensitivity and specificity of CEA measurements. Therefore, in general, only patients with advanced malignant disease show increased preoperative CEA serum concentrations.