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Eine vielfältige klinische und zellbiologisch-experimentelle Forschungslandschaft trägt dazu bei, dass gerade beim metastasierten Mammakarzinom die zunehmenden therapeutischen Alternativen einer medikamentösen Behandlung nicht nur einem steten Wandel unterworfen sind, sondern glücklicherweise auch zu einer schrittweisen Verbesserung der Langzeitergebnisse führen [1]. Wie bei der einzelnen Patientin zu verfahren ist, wird durch die onkologischen Therapeuten oft recht unterschiedlich beurteilt. Auch aus Sicht der Autoren sind bei den zahlreichen unterschiedlichen Situationen eines Langzeitverlaufs die Behandlungsmöglichkeiten heterogen. Diese können durch die gegenwärtige Studienmedizin nur teilweise abgebildet werden [2]. Deshalb sind Vorgaben durch vereinfachende Leitlinien von Fachgesellschaften auch nicht immer befriedigend.

Background:Cancer patients of the Department of Internal Medicine (Cancer Research) of the Essen University Medical School (Tumor Clinics), Germany, were examined and questioned with the aim of identifying those who run a high risk of deep vein thrombosis (DVT).

Dose escalation of chemotherapy has been shown to improve the prognosis of various malignancies; however, these therapies are associated with considerable morbidity requiring the use of intensive care medicine in some of these patients. The objective of this study was to assess the prognosis of cancer patients treated in an intensive care unit (ICU) and to identify clinical parameters which are predictive for their outcome. We performed a retrospective analysis of charts from 94 cancer patients admitted to an ICU over a five-year period. From these 94 cancer patients, 64 patients had a hematological malignancy, while 30 patients had a solid tumor. Ninety-two patients (98%) had already been treated with chemotherapy. The main reasons for ICU transferal were respiratory failure (49%), sepsis (21%), bleeding complications (7.4%), and cardiac decompensation (6.4). Mechanical ventilation and vasopressor therapy (noradrenaline, dopamine) were required in 68% and 66% of patients, respectively. The ICU and the in-hospital mortality rate was 55% and 67%, respectively. In multivariate regression analysis, respiratory failure requiring mechanical ventilation, serum level of lactate dehydrogenase, and multiple organ dysfunction assessed by the SOFA score were predictive for intensive care mortality, whereas respiratory failure requiring mechanical ventilation, multiple organ dysfunction assessed by the SOFA score, and the remission status of the underlying malignancy were predictive for overall survival. In conclusion, the main risk factors for death in an ICU are respiratory failure and multiple organ dysfunction, while the prognosis of the underlying malignancy becomes relevant for the long-term survival.

Purpose: We investigated whether increasing the patients’ processed blood volume (BV) during peripheral blood stem cell collection (PBSCC) from four to five times leads to a greater yield of CD34+ cells. We also studied the kinetics of CD34+38– and CD34+49d+ subsets and compared the amount of transfused cells with engraftment. Methods: All patients (n=20) received chemotherapy followed by G-CSF for PBSC mobilization. Samples from the patients’ peripheral blood and the PBSC harvests were taken after processing 1-, 4-, and 5 times the patients’ calculated BV. Results: The mean total yields of CD34+, CD34+38–, and CD34+49d+ cells were 15.69-, 1.13- and 4.17×106/kg body weight, respectively. The mean increase for these subsets between 4- and 5 BV was 10%, 8%, and 21%, respectively. Based on the mean number of 2.25 (range 2–3) planned courses of high-dose chemotherapy (HDC) per patient, the mean yield of CD34+ cells per kg body weight and intended course of HDC after 4- and 5 BV was 6.31- and 6.97×106(P=0.014). Twenty HDC were evaluable for engraftment. There was some correlation between the number of transfused CD34+ and CD34+38– cells and WBC engraftment (r= –0.66 and –0.69; P<0.01) and CD34+ cells and platelet engraftment (r= –0.56; P= 0.013). No toxicity occurred during PBSCC, although the mean platelet count dropped by 50% which must be kept in mind regarding the additional application of anti-coagulants and the fact that most patients had large indwelling catheters. Conclusion: Processing 4 BV is sufficient to collect >5×106CD34+ cells/kg body weight and intended course of HDC in most patients, although extension to 5 BV further increases the total yield of CD34+ cells.

We studied cytokeratin-positive (CK+) cells in the bone marrow (BM) and tumor markers (TM) in the blood of 128 patients with primary breast cancer in order to obtain an early diagnosis of residual disease. CK+ cells of two BM aspirations were detected by immunocytochemistry (IC). To evaluate the usefulness of immunomagnetic separation (IMS) for tumor cell enrichment in clinical samples, IMS was performed prior to IC and compared with the results for IC alone. The overall CK+ rate was 34% (44/128 patients), 29% (15/51) for patients with T1 tumors, 33% (28/84) for N0 patients and 31% (26/82) for patients with G1-2 breast carcinoma. Interestingly, 67% of CK+ patients were only positive in one of the two aspirates studied. A comparison between IC alone and IMS/IC could be performed in 70/128 patients (28/70 CK+). In 6/28 patients, CK+ cells were detected by both methods, in 16/28 patients only by IC and in 6/28 patients only by IMS. At least one TM, including carcinoembryonic antigen, carbohydrate antigen 15-3 and tissue polypeptide antigen, was increased in 58/128 (45%) patients [21/58 (36%) were CK+ in the BM]. Surprisingly, levels for the extracellular domain of Her-2/neuin serum samples were within the normal range in every patient studied. After a 2-year follow-up, 7/128 patients relapsed (3/7 CK+/TM−; 2/7 CK−/TM+; 2/7 CK−/TM−). We conclude that studying two BM aspirates for CK+ cells by IC in combination with TM determination is useful for identifying patients with a higher risk for relapse, however, tumor cell enrichment techniques will have to be improved for clinical use.

Maligne Keimzelltumoren gehören zu den prognostisch günstigen Malignomen des Erwachsenen. Dies gilt auch für fortgeschrittene Erkrankungsstadien. 70–80% der Patienten können auch in Stadien disseminierter Erkrankung mittels einer konventionell dosierten cisplatinhaltigen Kombinationschemotherapie sowie ggf. erforderlicher Resektion postchemotherapeutischer Residualtumoren geheilt werden [7, 10]. Die klinisch-wissenschaftlichen Therapiestrategien während der vergangenen 5–10 Jahre konzentrieren sich daher auf diejenigen 20–30% der Patienten, bei denen mit diesem Vorgehen keine dauerhafte Tumorfreiheit erreicht werden kann, sei es infolge unzureichenden Ansprechens auf die primäre Chemotherapie oder durch späteren Tumorrückfall bzw.-progression. Neben der Prüfung neuerer Zytostatika wurden international während der letzten 10 Jahre schwerpunktmäßig die Wirksamkeit und die Toxizität der hochdosierten Chemotherapie geprüft. Aktuelle Fragen hinsichtlich des Stellenwerts bei Patienten mit malignen Keimzelltumoren konzentrieren sich u.a.auf die mögliche Bedeutung in der Primärtherapie, bei unzureichendem Ansprechen auf die Initialtherapie sowie des geeigneten Zeitpunkts ihrer Anwendung im Rezidiv bzw.bei Therapieversagen. Diesen Aspekten wird derzeit in prospektiven rando-misierten Studien nachgegangen.

Purpose: Although gene transfer with retroviral vectors has already been applied to patients as part of clinical protocols, low expression of transgenes in target cells still remains a problem. Therefore, we compared various retroviral vectors using different promoters and backbones for expression of the enhanced green fluorescent protein (EGFP) reporter gene in fibroblasts and CD34⁺ cells. Methods: The N2A retroviral vector was used to test expression from the herpes simplex virus thymidine kinase promoter (vector N2A-TK-EGFP), a human phosphoglycerate kinase promoter (vector N2A-PGK-EGFP), and the SV40 promoter (vector N2A-SV-EGFP). Additional constructs used the spleen focus-forming virus (SFFV) long terminal repeat (LTR) as promoter and expressed EGFP alone (vector SF1-EGFP) or EGFP and a downstream (vector SF1-EGFP-IRES) or upstream (vector SF1-IRES-EGFP) internal ribosomal entry site. Results: For NIH 3T3 cells the fluorescence-activated cell sorting analysis revealed that the most active internal promoter was the SV40 promoter in the vector N2A-SV-EGFP (mean fluorescence intensity, MFI, 66.7 0.4), followed by N2A-PGK-EGFP (26.3 1.8 MFI), and N2A-TK-EGFP (4.8 0.1 MFI). Expression from the SF1-EGFP vector (82.6 6.7 MFI) and the SF1-EGFP-IRES vector (102.8 6.2 MFI) was higher than from SF1-IRES-EGFP vector (15.5 1.8 MFI). In human CD34-positive cells, the EGFP expression from all vectors was considerably lower than in fibroblasts with the SF1-EGFP vector still being four- to fivefold more active than the internal promoters tested. Conclusion: The SFFV LTR seems to allow a high expression of transgenes, as long as the transgene is not expressed downstream of an internal ribosomal entry site. Internal promoters may be useful for targeted gene expression in specific cell types, but the reduced level of expression from some internal promoters has to be taken into consideration.

Abstract: Purpose: Modulation of DNA repair represents one strategy to overcome cellular drug resistance to alkylating agents and platinum compounds. The effects of different known DNA repair modulators such as O 6-benzylguanine (6 μg/ml), fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 μg/ml) and methoxamine (12.4 μg/ml) on the cytotoxicity of mafosfamide, chlorambucil, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin and carboplatin were tested in human lung cancer cell lines. Methods: Chemosensitivity of the human adenocarcinoma cell line MOR/P and the cisplatin-resistant subline MOR/CPR as well as the large-cell lung cancer cell line L23/P and its cisplatin-resistant counterpart L23/CPR were evaluated by the MTT colorimetric assay. Results: O 6-benzylguanine, an inhibitor of O 6-alkylguanine-DNA alkyltransferase, significantly sensitised MOR/P and MOR/CPR cells to the cytotoxic effect of BCNU. Fludarabine, methoxamine and aphidicolin did not change the chemosensitivity of the parental and cisplatin-resistant cell lines to any cytotoxic drug tested. Interestingly, O 6-benzylguanine enhanced the chemoresistance of parental and cisplatin-resistant cell lines to platinum compounds. Also, pentoxifylline increased resistance of the MOR cell lines to mafosfamide. Conclusions: Modulation of DNA repair elicits not only chemosensitisation but may also enhance cellular resistance to DNA-affine drugs.

The purpose of this randomized phase III trial was to study whether medroxyprogesterone acetate (MPA) maintenance treatment prolongs the time to progression in advanced breast cancer patients responding to an induction chemotherapy. Patients with progressive advanced breast cancer previously untreated with anthracylines and progestins were given epirubicin (30 mg/m2) and ifosfamide (2 g/m2) on days 1 and 8 at 3‐weekly intervals. Patients without disease progression after 6 cycles of chemotherapy were randomly assigned to receive, until progression, either no treatment or MPA at a daily total dose of 500 mg. Ninety patients were randomized: 46 to the MPA arm and 44 to the observation arm. Median time to progression was longer in the MPA arm: 4.9 months versus 3.7 months in the intent‐to‐treat analysis (p=0.02), and 4.9 months versus 3.0 months in the secondary efficacy analysis (p=0.012). Seven patients were removed from MPA due to side effects. The changes in patient‐rated quality of life scores were similar in both groups. The median length of survival from randomization was 17.4 months for patients receiving MPA and 18.3 months for patients randomized to observation (p=0.39). In conclusion, in patients with advanced breast cancer achieving remission or non‐progression with 6 cycles of epirubicin and ifosfamide chemotherapy, MPA maintenance treatment led to a significant, though modest, prolongation of the time to progression without affecting overall survival of the study patients.

Thrombopoietin (TPO) serum levels in 14 patients (9 male and 5 female, mean age 36 years, range 16 to 55 years) with breast cancer (n = 5), testicular cancer (n = 7), or lymphoma (n = 2), undergoing high dose chemotherapy with peripheral blood stem cell (PBSC) transplantation, were evaluated at the first day of the mobilization chemotherapy (1), at the day of the first apheresis (2), and at the day of stem cell transfusion (3). All patients have been pretreated (one to four regimens) and received chemotherapy and granulocyte colony stimulating factor (G‐CSF) or granulocyte‐macrophage colony stimulating factor (GM‐CSF) both at 5 μg/kg body weight (bw). for stem cell mobilization. TPO was measured with a human TPO immunoassay.

Summary Thirty-eight pretreated patients with primarily resistant [6] or relapsed [32] small-cell lung cancer were treated with a combination of vindesine (3–4 mg/m2) and cisplatin (60–100 mg/m2). Eight patients responded to this therapy with three (8%) complete and five (13%) partial remissions. Minor responses were noted in 12 (32%) additional patients. Chemotherapeutic response was rare in regions of prior irradiation. In the complete remission group survival from start of vindesine/cisplatin therapy lasted 61, 48 and 38 weeks, respectively. In the “less-than-complete-remission” group median survival was 12 weeks. Nausea and vomiting were the prominent side-effects, while only mild to moderate myelosuppression was noticed in most cases. The vindesine/cisplatin combination showed significant activity in heavily pretreated small-cell lung carcinoma. However, the remission rates remain low in this unfavourable condition, which might be due to pronounced chemotherapeutic resistance in previously irradiated areas.

Summary Since July 1978 one hundred and three consecutive patients with unresectable small cell bronchogenic carcinoma were treated with a combination of doxorubicin, cyclophosphamide and vincristine (ACO). In limited disease patients (64) the second chemotherapy course was followed by prophylactic cranial irradiation, the fourth by irradiation towards primary disease sites. Complete responders were randomised to either receive etoposide or no further maintenance therapy. Objective responses were reached in 88/100 evaluable patients, with 72% of complete remissions in limited-stage disease and 33% in extensive disease, respectively. The actuarial median survival time for limited disease patients was 15.8 months compared to 9.3 months in extensive disease (p<0.005). 29 of the 100 patients remain still alive, 4 for more than 24 months without disease recurrence. The survival advantage of patients reaching complete remissions relative to those who did not is highly significant (p<0.001). Acute gastrointestinal and hematological side effects were common, with possibly three drug-related deaths from infections during transient granulocytopenia (mean nadir: 600–900 cells/mm3). The present induction regimen using only four courses of chemotherapy produces high complete remission rates on roentgenography and bronchoscopy and improved survival in the majority of patients. Thus far any effectiveness of etoposide-maintenance therapy following ACO could not be substantiated.

Abstract: A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1–14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials.

The impact of the separated volume on the yield of CD34+ cells during peripheral blood stem cell collections (PBSCC) remains controversial. We therefore studied the CD34+ cell concentration in the peripheral blood of patients (pts) during PBSCC as well as the total amount of CD34+ cells collected after each blood volume (BV) processed and engraftment data for each cycle of high dose chemotherapy (HD Ctx).

Summary Sixty-two patients with metastatic soft tissue sarcomas of various histological types were treated with Cyvadic. No chemotherapy had been given previously. Complete remission (CR) was obtained in 10 % and complete plus partial remissions (PR) in 20 % of the patients. Mean duration of CR was 25 months, that of PR 2.5 months. Median survival time of r esponders was 28 months, that of nonresponders 14 months. Chemotherapy with a combination of ifosfamide plus cisplatin given to patients with primary or secondary resistance to Cyvadic led to CR + PR in 50 % of the patients.

Summary A 4-day colorimetric tetrazolium dye (MTT) assay was used to assess the cytotoxicity of adriamycin (ADM), vincristine (VCR), and idarubicin (IDA) in blasts isolated from 37 patients with newly diagnosed and pretreated acute myeloid leukemia (AML). The effect of verapamil (VRP) as a chemosensitizer was studied in relation to the expression of the membrane efflux pump P-glycoprotein (PGP) as determined by a semiquantitative flow-cytometric procedure. A slight positive correlation was found between the fraction of cells expressing PGP and the ID50 values for ADM and VCR, but not between cellular PGP content and sensitivity to IDA. The overall data showed no significant sensitization effect of VRP. However, in specimens with more than 10% cells expressing PGP, 2µM VRP sensitized cells to ADM and VCR significantly. The median of sensitization ratios (SRs), i.e., the ratios of cytotoxic drug ID50 in the absence/presence of VRP, were 1.89 and 2.0, respectively. No sensitizing effect of VRP on the cytotoxicity of IDA was observed. Related to the clinical status, the median fraction of PGP-positive blasts was elevated fourfold in pretreated patients (n=16) in comparison to patients with de novo AML (n=19). No differences in ID50 values were observed between newly diagnosed and pretreated patients. However, SRs for ADM and VCR were higher in samples of pretreated patients compared with de novo AML. PGP-mediated cellular drug resistance may thus be circumvented in leukemic blasts by application of chemosensitizers or, potentially, alternative anthracyclines.

Summary During long-term interferon a-2b (IFN) therapy of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) patients, short-term effects of tumor necrosis factor a (TNF) on peripheral leukocyte counts, as well as cortisol and corticotropin (ACTH) release were studied. TNF (40–160µg/m2) was given as a 2-h infusion on 5 consecutive days every 3 weeks, in addition to s.c. daily IFN injections (4 mio U/m2), to four (two male/two female) patients, who had been treated for more than 8 months with IFN and additionally for 0–7 months with TNF. Leukocyte counts, cortisol, and ACTH were determined at 30-min intervals between 4 p.m. and midnight. Profiles were determined the day before and on day 1 of TNF therapy. Leukocyte numbers decreased 30 min after start of TNF administration and increased 30–60 min later with a rebound until the next TNF application. The increase of leukocyte counts was due mostly to neutrophil granulocytes. ACTH levels increased 30 min, cortisol 60 min, and leukocyte counts 90 min after start of TNF infusion. Metopirone, an inhibitor of cortisol synthesis given to one patient, suppressed the TNF-induced stimulation of cortisol secretion and subsequent increase of leukocyte counts, while ACTH blood levels were enhanced. It was concluded that leukocyte count increases after TNF/IFN administration might be related to TNF-evoked cortisol secretion.

Summary Improved chemotherapeutic results have been obtained recently with combinations of 5-fluorouracil, adriamycin, and mitomycin or a nitrourea derivative. The response rates have been raised to 40%, and the median survival rate of responding patients has been increased to over 12 months. Regional disease should be treated by chemotherapy plus irradiation. Patients with curative resections are receiving adjuvant chemotherapy with improved regimens in various ongoing studies.

Summary Antitumor activity (increase in lifespan and cure) was greater for ifosfamide (IFO) in several experimental tumors, some of which were primarily resistant to cyclophosphamide (CYC).

We present the case of a 39-year-old man with Klinefelter's syndrome and metastatic Leydig cell carcinoma in whom autonomous cortisol production induced by the interstitial cell tumor was found. Apart from the Cushing's syndrome the endocrine activity of the tumor was demonstrated by the secretion of estradiol, estrone, alkaline phosphatase, and testosterone. This is, to our knowledge, the first description of a Cushing's syndrome not caused via ACTH production but directly induced by ectopic steroid production. While being resistent to chemotherapy and radiation, the tumor responded favorably to treatment with o,p'-DDD. The reduction of tumor size was accompanied by a continuous decrease of serum markers.

Bei einer Daunomycin-sensiblen und-resistenten Ehrlich-Aszites-Linie wurde die Kinetik der intrazellulären und intranucleären Inkorporation verschiedener neuer Anthracyclin-Derivate untersucht. Die Substanzen wurden aus gewaschenen Zellen oder gereinigten Zitronensäure-Zellkernpräparaten quantitativ extrahiert und fluoreszenzoptisch bestimmt. Unter “steady state”-Bedingungen war die intrazelluläre und intranucleäre Konzentration von Adriamycin und Daunomycin gleichermaßen um etwa 50% in der resistenten Zellinie vermindert. Marcellomycin und Carminomycin hingegen waren nur um 5% bzw. 9% gegenüber der sensiblen Linie vermindert konzentriert, während Aclacinomycin und AD 32 in beiden Zellinien gleichermaßen inkorporiert und retiniert wurden. Beim Vergleich der intranucleären zur intrazellulären Konzentration fand sich bei AD 32 eine vorwiegend zytoplasmatische Lokalisation, während Aclacinomycin und Carminomycin zum größten Teil (78% bzw. 74%) und Marcellomycin fast ausschließlich im Zellkern konzentriert wurden. Diese Werte korrelierten zwar mit der gleichzeitig bestimmten Hemmung des Thymidin-Einbaus, jedoch nicht mit der Zytotoxizität und weisen somit daraufhin, daß neben der intranucleären Konzentration der Anthracycline und ihrer Bindung an die DNA mit konsekutiver Hemmung der DNA-Replikation noch andere Faktoren für die durch Anthracycline bewirkte Zytotoxizität infrage kommen müssen.

4'-Epi-doxorubicin is a new anthracycline analog with reduced cardiac toxicity in animal studies. A phase-II study was performed in 17 patients predominantly with non-small-cell lung cancer. All suffered from recurrent or advanced tumors and 7 of 16 evaluable patients had been pretreated with an alternative chemotherapy. 4'-Epi-doxorubicin was applied at a dose of 75 mg/m2 every 3–4 weeks. The median total dose was 280 mg (range: 130–250 mg). Only one patient with epidermoid lung cancer (overall response rate: 6%) showed a minor response and stable disease was observed in six other patients with bronchogenic carcinoma. Myelosuppression was rare and moderate: Leukocytopenia of less than 2,000/mm3 occurred in 25% of patients and thrombocytopenia of less than 100,000/mm3 in 8% of patients. The frequency of alopecia and gastrointestinal side effects was 88% and 80%, respectively. Persistent electrocardiographic alterations were recorded in 2 of 14 (14%) patients. One of four patients revealed a marked reduction of left ventricular ejection fraction in radionuclide cardiography. It is concluded that 4'-epi-doxorubicin is not superior to adriamycin in this low-prospect treatment area, but studies with increased doses appear necessary in adriamycin-sensitive tumors because of recent reports from phase-III trials showing reduced cardiac and gastrointestinal toxicity with 4'-epi-doxorubicin in comparison with adriamycin.

Fünfundzwanzig Patienten mit metastasierendem malignem Melanom und gut dokumentierbaren Tumorparametern wurden mit einer kombinierten zytostatischen Chemotherapie, bestehend aus Cisplatin und Ifosfamid, behandelt. Cisplatin wurde an den Tagen 1, 3, 5, 7 und 9 in der Tagesdosis von 30 mg und Ifosfamid in einer Dosis von 45 mg/kg an den Tagen 2, 4, 6, 8 und 10 verabreicht. Die meisten Patienten waren zuvor mit DTIC oder DTIC-haltigen zytostatischen Kombinationen behandelt worden. In drei Fällen wurde eine komplette Remission und in sieben Fällen eine Teilremission mit über 50% Tumorreduktion erreicht. Die mittlere Überlebenszeit betrug für therapieresistente Fälle 3 Monate und für Ansprecher 6 Monate. Erbrechen und Übelkeit während der Behandlung konnte durch die Verabreichung von Levomepromazin (Neurocil) reduziert werden. Die hämatologische Toxizität war bei intensiv vorbehandelten Patienten erheblich und machte eine Verlängerung des therapiefreien Intervalls in zwei Fällen erforderlich.

Unter stationär-klinischen Bedingungen wurde die zufällig beobactete antiemetische Qualität des oral angewandten Phenothiazinderivats Levomepromazin bei Tumorpatienten untersucht, welche entweder mit Cisplatin, Iphosphamid oder Adriamycin-haltigen Kombinationen behandelt wurden.

Ring unsubstituted dichloro(diphenylethylenediamine)platinum(II) complexes show a dependence of their antitumor activity on the configuration and position of phenyl rings in ethylenediamine ligand. Dichloro(1,1-diphenylethylenediamine)platinum(II) (1d) and meso-dichloro(1,2-diphenylethylenediamine)-platinum(II) (meso-2d) have a weaker effect on the human breast-cancer cell line MDA-MB 231 and on rat leukemia L5222 than (±)-dichloro(1,2-diphenylethylenediamine)platinum(II) ((+)-2d) and its enantiomers (+)-2d and (-)-2d which cause marked and comparable inhibition of both tumors; (±)-2d is also active on ADJ/PC 6 plasmacytoma of the mouse and on cisplatin-, daunomycin-, and cisplatin/daunomycin-resistant Ehrlich ascites tumors of the mouse. The differences in activity of the diastereomers (±)-2d and meso-2d, for which distinct influences on the DNA secondary structure can be demonstrated CD spectroscopically may be explained by a steric hindrance of the drug-DNA interaction.

Seventy-three evaluable patients with advanced measurable solid tumors were given cisdichlorodiammineplatinum (II) (DDP) at a dose of 20 mg/M2 IV for 1–5 days every 3 weeks, and 19 patients who failed on this low dose DDP protocol received a single high dose of 100 mg/M2 IV once every 3 weeks. Forty-six patients had received prior chemotherapy, and 29 patients were untreated. Results included four complete responses (5.5%) in malignant melanoma, spindle-cell sarcoma, adrenal carcinoma, and bladder carcinoma lasting 2 to 4 months. In 21 patients (28.8%), partial responses were achieved. Twenty-two patients (30.1%) showed stable disease and 26 (35.6%) had tumor progression. A response rate of 25% (4/16 patients) was found for malignant melanoma, 45.5% (5/11) for nonsmall-cell lung cancer, and 35.3% (6/17) for sarcomas of various types. One patient with teratocarcinoma, who relapsed on low-dose DDP, had another partial remission for 4 months after high-dose therapy. Toxicity was most commonly seen with gastrointestinal side effects and myelosuppression. Cumulative nephrotoxicity was prevented by prehydration and/or treatment with furosemide or mannitol.

Summary The cytostatic efficacy of the antibiotics adriamycin, daunomycin and actinomycin D and of DNA-complexes of these compounds was compared in an Ehrlich ascites tumor in vivo. Various doses of the individual drugs and their DNA-complexes were injected intraperitoneally into female NMRI mice following 8 days after inoculation of 106 Ehrlich ascites cells. Survival analyses of animals demonstrated that by addition of DNA therapeutic indices were improved for adriamycin, daunomycin and actinomycin D. DNA alone had no effect on this tumor. Since earlier biochemical data (Seeber et al., 1977) had shown decreased in vitro cytotoxicity of DNA-bound antibiotics, this increase in therapeutic efficacy is probably due to an altered pharmacological behaviour after complex formation with a prolongation of effective intraperitoneal drug levels and decreased systemic toxicity.

Summary: Background Until recently, chemotherapy of gastric cancer was regarded as only marginally active when used with palliative intention or perioperatively. MethodsThis is a critical review of the chemotherapy trials being published in gastric carcinoma since 1980.ResultsDuring the past 10 years a number of new and active combinations had been developed, which induced 40 to 60% of objective remissions (mostly in phase-II-trials) and up to 10% of clinically complete remissions (in part pathologically confirmed) in locally advanced or metastasized tumors. With these regimens, median survival times of 9 to 11 months were achieved. Moreover, it was shown that a chemotherapy induced reduction of local tumor spread may allow R0-resection of primarily irresectable disease and that chemotherapy can be also used with curative intention. ConclusionsBecause of these results, gastric cancer can be regarded as a chemosensitive tumor.

The effects of 300 kV X-rays, 60Co γ-rays, 43 MV X-rays and 43 MeV electrons on total cell RNA and 45 S pre-r RNA were investigated in Novikoff Hepatoma ascites cells. Six hours after local irradiation of the animals with 600 rad, the tumour cells were labelled in vivo for 30 and 60 min. The specific activities of high-molecular-weight RNA were influenced differently. This may be due to divergent effects of the applied radiation qualities at the level of transcription and transformation (processing). In addition, these radiation effects are mediated by the adrenal glands in a rather complex manner. Therefore, the results presented in this study support the suggestion that an in vivo labelling system is unsuitable for the evaluation of quantitative radiation effects on RNA.

Interferon (IFN) therapy has become widely used for the treatment of chronic myelogenous leukemia. Hematologic remissions can be induced in about 60% of patients. Moreover, in a small number of patients loss of the Philadelphia (Ph) chromosome and of the BCR-ABL rearrangement is observed. We have used genomic Southern blotting as well as a two-step polymerase chain reaction (PCR) method to score for BCR-ABL messenger RNA (mRNA) in patients with hematologic remission induced by treatment with IFN alpha-2b alone or in combination with IFN gamma. Concomitantly, cytogenetic analysis was performed. In 11 of 115 patients reported here, a complete loss of rearranged BCR fragments was observed in Southern blots of peripheral blood (PB) and/or bone marrow (BM) cell samples. Malignant marker bands disappeared first in the PB. In six patients, this genotype remained stable, whereas in five patients, low-intensity, rearranged bands reappeared despite continuation of treatment. The reappearance of the malignant marker was not accompanied by a clinical relapse. Ph-negative metaphases were observed in PB cells of four patients and in the PB and BM cells of two of these patients. In the samples of the other patients, residual Ph- positive cells were detected. By two-step PCR, residual BCR-ABL rearranged transcripts were found in samples of 10 patients.

Response to chemotherapy and survival was retrospectively analyzed in 28 patients with bulky retroperitoneal and disseminated seminoma treated between 1977 and 1983. The median age was 41 years (range: 23-52). All patients had histological evidence of pure testicular seminoma, however, 14 patients revealed moderate increases of human beta-chorionic gonadotropin levels. Prior radiotherapy had been given to 9/28 (32%) patients. Treatment consisted of at least four courses of simultaneous or sequentially alternating therapy with cisplatin, vinblastine, bleomycin plus/minus adriamycin (PVB +/- A), administration of ifosfamide or combination therapy with ifosfamide/cisplatin (IFS/DDP) or ifosfamide/etoposide (IFS/ETP). Twenty-five of 28 patients (89%) achieved a complete (CR), and 3/28 patients a partial remission. Relapse occurred in 1/8 CR patients after adjuvant postchemotherapeutic irradiation, and in 1/11 patients without any further radiotherapy. So far, 23/28 patients (82%) are free of disease after a median follow-up of 28+ (14+----82+) months. Marked myelosuppression was observed in previously irradiated patients, mainly after PVB +/- A therapy. In two patients, transient nephrotoxicity developed after PVB and IFS/DDP, respectively. After PVB +/- A chemotherapy, three patients revealed polyneuropathy, paralytic subileus and bleomycin-induced pneumonitis, respectively. In conclusion, the present series suggests a high probability of continuous CR in even bulky retroperitoneal and widespread metastatic seminoma. So far, no definite conclusions can be made on the therapeutic superiority of one of the different chemotherapeutic regimens used. However, this preliminary experience suggests that the combination of ifosfamide and etoposide or cisplatin may prove less toxic than sequentially alternating or simultaneous PVB +/- A chemotherapy.

Summary Praetherapeutic sensitivity tests of human solid tumours based on incorporation studies of nucleic acid precursors have been described by various authors. This review intends to show that such tests may only be of rather limited value for the design of individual chemotherapeutic regimens. In many drugs, a correlation between biochemical and clinical effects has not yet been established. The reliability of praetherapeutic sensitivity tests is further impaired by general methodological difficulties of short-term cultures, individual pharmacology and toxicology of cytostatic agents as well as pharmacological and biochemical drug interactions in combination chemotherapy. Praetherapeutic testing with individual cytostatic drugs is discussed.

Summary Following orchiectomy and retroperitoneal lymph node dissection (RND) 140 patients with stage II non-seminomatous testicular cancer were treated by sequential combination chemotherapy consisting of vinblastine/bleomycin and adriamycin/cis-dichlorodiammineplatinum(II) (DDP), plus/minus radiotherapy. 68 stage IIA-patients (complete RND and normal tumor-markers thereafter) received 6 courses of chemotherapy, followed by radiotherapy in 35 patients. 40 stage IIB-patients (minor residual disease after RND or elevated tumor-markers after RND) and 32 stage IIC-patients (advanced residual disease after RND) were treated by at least 12 chemotherapy courses and optional intermittent radiotherapy and/or relaparotomy. In stage IIA and IIB disease the actuarial 4-year survival rates were between 80 and 100%. These favourable results were not significantly influenced by additional radiotherapy and corresponded to the survival rates for 34 stage I-patients. For stage IIC-patients the prognosis was significantly worse with a 12% 4-year survival rate.

Summary 74 patients with disseminated non-seminomatous testicular cancer were randomly entered on a prospective sequential combination chemotherapy regimen with mandatory crossover, consisting of either vinblastine/bleomycin or adriamycin/cis-dichlorodiammineplatinum (II) (DDP) as initial therapy. Independent of the randomization the overall remission rate in 71 evaluable patients was 89% including 54% complete remissions. 35% of the patients remained disease-free at 2+ to 28+ months with a median of 12 months. By additional surgical removal of residual pulmonary metastases in two patients the complete remission rate was increased to 40/71 (56%), and the number of patients with no evidence of disease to 27/71 (38%). According to the life-table method the two-years survival rates were 63% for complete responders and 29% for all other patients, which was significantly lower. 53 patients (75%) were alive at 3 to 28 months with a median of 9 months. Additional advanced abdominal disease, initially elevated ß-HCG and LDH and extension of pulmonary disease were of significant negative influence on the prognosis. The evaluation of single chemotherapy courses revealed equal efficacy of both combinations. However, response to adriamycin/DDP occurred in 46% of the courses, when vinblastine/bleomycin had failed, while response to vinblastine/bleomycin occurred only in 21% of the courses when adriamycin/DDP had failed. Thus different patterns of cross-resistance between these alternative regimens may exist.

Zusammenfassung Phenol-lösliche Chromatinprotein wurden aus Zellkernen normaler und leukämischer menschlicher Leukozyten isoliert. Die Proteine, deren Bedeutung im Rahmen der Kontrolle des Transkriptionsvorganges diskutiert wird, wurden durch Analyse ihrer gelelektrophoretischen Verteilungsmuster und ihrer Markierung mit14C-Leuzin oder32P-Orthophosphat verglichen. Außerdem wurde der Einfluß interkalierender Agentien wie Adriamycin untersucht.

Summary Recent studies on the molecular biology of the lymphocyte of chronic lymphocytic leukemia confirm the neoplastic nature of these cells. Functional and structural differences in the biochemistry of DNA, RNA and proteins define the biological peculiarity of this disease in which oncorna viruses are probably of no pathogenetic importance. Cells of chronic lymphocytic leukemia are characterized by various macromolecular abnormalities: multiple DNA-polymerases after PHA-stimulation, decreased actinomycin binding capacity, altered transcription of the chromatin, elevated DNA-repair, increased RNA-synthesis, increased synthesis of ribosomal precursors combined with a failure in ribosomal maturation, different32P nucleotide composition and oligonucleotide frequencies of nuclear 45S RNA and ribosomal 28S RNA, impairment in stimulation of nucleolar “processing” by PHA, decreased lysosome and polysome content, functional impairment of ribosomes in cell-free systems, new hybridizable polyribonucleotide sequences in nuclear heterogeneous RNA as well as qualitative and quantitative differences in the nuclear proteins after two-dimensional mapping by gel electrophoresis. The interpretation of the CLL-lymphocyte as a B-like cell does not seem to be sufficient with respect to the new biochemical data.

Aclacinomycin A (ACM) is a new anthracycline antibiotic with a reduced cardiac toxicity in animal models. A phase II study was performed in a total of 25 patients, 23 of whom are evaluable for response. All suffered from recurrent and advanced tumors. Pretreatment consisted of at least four different chemotherapeutic agents (range: 4–9). Lung cancer patients (3/9) were irradiated to the mediastinum. Eighteen patients were pretreated with doxo- or daunomycin. The dose for solid tumors was 2–3 mg/kg given on 3 consecutive days every 3 weeks. Leukemia patients received a daily dose of 20 mg/m2, and standard response criteria were used. Marked reductions of leukocyte counts were achieved in leukemia patients. The overall response rate was about 15% in solid tumors, but major objective responses (CR+PR) have not been observed. Myelosuppression was commonly moderate in solid tumor patients, nausea and vomiting were rare, and alopecia was not induced. Cumulative cardiotoxicity was not evaluated in this trial. Treatment with ACM requires further investigation in acute leukemias and solid tumors, not pretreated with anthracycline antibiotics.