Vinorelbine after paclitaxel in breast cancer: cross resistance and cumulative neurotoxicity?
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Antineoplastic Agents↗
Biomedical subjects
C Dittrich
Publications and source records attributed to C Dittrich.
In vitro and in vivo evaluation of the combination of cisplatin and its analogue carboplatin for platinum dose intensification in ovarian carcinoma.
BACKGROUND: Cisplatin and its analogue carboplatin have been shown to cause dose-dependent growth inhibition throughout a wide dose range in the ovarian cancer cell lines OVCAR-3, 2780, HTB-77, and CRL-1572 tested. Cisplatin was 30 times more effective than carboplatin. The combination of both substances led to a less-than-synergistic effect, as was revealed by an isobologram in the OVCAR-3 cell line. Because of the different toxicity pattern, cisplatin and carboplatin theoretically are ideal candidates for combination chemotherapy in platinum-sensitive tumors. METHODS: In a Phase II study, the efficacy, the toxicity profile, and the feasibility of combining both substances were assessed in 20 previously untreated patients with ovarian cancer. The regimen consisted of carboplatin (300 mg/m2) on day 1, followed by cisplatin (100 mg/m2) on day 2 every 4 weeks. RESULTS: A total of 81 cycles were administered (median, 4 cycles; range, 1-6 cycles); four patients experienced complete remission and three experienced clinical partial remissions. Limiting toxicities were thrombocytopenia, leukopenia, and ototoxicity. The mean (+/- standard deviation [SD]) carboplatin and cisplatin dose intensities (DI) reached during the first four cycles of therapy were 58 mg/m2/week (+/- 18 mg/m2/week) and 21 mg/m2/week (+/- 7 mg/m2/week), respectively, which corresponded closely to the projected DI of 75 and 25 mg/m2/week, respectively. Based on the equivalence ratio of 4:1, the DI of carboplatin has been converted into the respective cisplatin DI, resulting in a total DI estimate. The overall DI of 37 mg/m2/week (+/- 14 mg/m2/week) was close to the projected one of 44 mg/m2/week. CONCLUSIONS: Combining cisplatin with carboplatin was found to represent a feasible and efficacious therapeutic strategy for increasing platinum dose intensity.
Anemia↗
Modulation of the immunophenotype of ovarian cancer cells by N,N-dimethylformamide and transforming growth factor-beta 1.
Exposure of HOC-7 ovarian adenocarcinoma cells to regulators of cell differentiation caused inducer-dependent alterations of the antigenic pattern of the cells. Immunocytochemistry revealed that N,N-dimethylformamide (DMF) elevated the membrane staining for epidermal growth factor (EGF)-receptor and for desmoplakins I and II. DMF also stimulated cytoplasmic and surface labeling for CA 125 and the deposition of fibronectin into the extracellular matrix. Stimulation of fibronectin was also seen after addition of transforming growth factor (TGF)-beta 1. These responses were quantified using a fixed-cell, enzyme-linked immunosorbent assay (ELISA) and revealed that DMF dose-dependently induced expression of EGF-receptor, CA 125, fibronectin, and desmoplakins I and II. TGF-beta 1 stimulated fibronectin and desmoplakins I and II only. Production of EGF and TGF-alpha was not affected by these inducers. Immunocytochemistry, ELISA and Western blotting showed that both inducers caused down-regulation of myc oncoproteins. DMF was more effective in changing the immunophenotype of HOC-7 cells than TGF-beta 1. Desmoplakins I and II demonstrated elevated epithelial differentiation, whereas fibronectin indicated stimulation of extracellular matrix formation. Elevated EGF-receptor could not compensate for the growth inhibition induced by DMF. The expression of myc oncoproteins was inversely related to cell proliferation. CA 125, however, seems to be unrelated to cell growth.
Blotting, Western↗
Retinoic acid receptors in retinoid responsive ovarian cancer cell lines detected by polymerase chain reaction following reverse transcription.
The growth inhibitory effects of all-trans and 13-cis retinoic acid (RA) and of the synthetic retinoids TTNPB, TTNPB-ethylester and TTNN were studied on seven human epithelial ovarian cancer cell lines and one ovarian teratocarcinoma cell line. Six of seven ovarian adenocarcinoma cell lines were inhibited in their growth by RA and by synthetic retinoids in a dose dependent manner. No response to these substances was observed for the ovarian teratocarcinoma cell line. The knowledge that RA and retinoids exert their action on the cells via nuclear receptors led us to examine the expression of RAR-alpha, -beta and -gamma mRNA by these cell lines by polymerase chain reaction following reverse transcription. All cell lines expressed RAR-alpha and -gamma mRNA and six of the eight cell lines were found to express additionally RAR-beta mRNA, among them the ovarian teratocarcinoma cell line. Our data indicate that there was no direct association between the presence of RAR subtype transcripts and the response to retinoids in ovarian cancer cell lines.
Adenocarcinoma↗
Etoposide and carboplatin as salvage and first-line therapy in ovarian cancer patients.
BACKGROUND: The agents etoposide and carboplatin are active against ovarian cancer and display synergistic anti-tumor activity in animal tumor models. The objective of these two phase II trials was to determine the efficacy and toxicity of the combination of etoposide with carboplatin in previously treated and untreated patients with ovarian cancer. PATIENTS AND METHODS: Etoposide (100 mg/m2) was administered as a one-hour infusion on three consecutive days and carboplatin (400 mg/m2) as a 30-minute infusion on day 2 of each monthly scheduled cycle. In 20 patients, previously treated with cisplatin-containing regimens, a total of 102 cycles was applied as salvage therapy (ST) and in 27 patients, a total of 168 cycles as first-line therapy (FLT). RESULTS: ST yielded 2 complete remissions (CR) and one partial remission (PR); in 7 patients, no evidence of disease (NED) and in 6 patients, no change (NC) were observed. The progression-free intervals (PFI) lasted a median 7.0 months (range < 2-14 months). FLT resulted in 7 CR (4 of them pathologically (p) verified), 11 NED (1 pNED), 3 PR (1 pPR) and 6 NC. The objective response rate was 63% (95% confidence interval: 36-89%). PFI lasted a median 8.0 months (range 3-25+ months); median survival had not been reached at the time of evaluation. Thrombocytopenia (WHO grade 4) was the limiting toxicity. CONCLUSIONS: Although not fulfilling the expectations of synergistic activity as shown in preclinical models, the combination of etoposide with carboplatin is an active and feasible therapy regimen in the out-patient management of ovarian cancer.
Adult↗
Different propensity for spontaneous differentiation of cell clones isolated from the human ovarian surface epithelial cell line HOC-7.
Limiting dilution culture of cell fractions obtained by discontinuous density gradient centrifugation was used to establish six different cell clones from HOC-7 ovarian adenocarcinoma cells (D1-D3, N1-N3). Clones D1-D3 revealed a phenotype similar to that seen in parental cells exposed to differentiation inducers such as dimethyl sulfoxide (DMSO, 0.8% [v/v]). They were flattened, slowly growing cells (doubling times: 42-46 h). The cells developed long cytoplasmic extensions and adopted a complicated growth pattern. Fixed-cell enzyme-linked immunosorbent assay (ELISA) and Western blotting demonstrated that these cells contained high levels of epidermal growth factor-receptor (EGF-R), carbohydrate antigen 125 (CA 125), fibronectin and desmoplakin, but low levels of myc oncoproteins. However, untreated parental cells and clones N1-N3 were fast-growing (doubling times: 23-28 h), regularly shaped, polygonal cells ("cobblestone" monolayer) with low levels of EGF-R, CA 125, fibronectin and desmoplakin, but relatively higher amounts of myc oncoproteins. The similarity of the sublines to either untreated or inducer-treated parental cells indicated that clones D1-D3 represented spontaneously differentiated HOC-7 cells, whereas clones N1-N3 originated from less-differentiated cells. The features examined in this model cell system proved to be closely related to ovarian cancer cell proliferation and differentiation. The observation of a tumor-inherent propensity for spontaneous differentiation suggests that exogenous stimulation of existing differentiation pathways may represent an alternative approach for tackling the problem of growth control and differentiation in malignant tissues.
Adenocarcinoma↗
[High-dose epirubicin in combination with high-dose ifosfamide plus granulocyte colony stimulating factor in patients with advanced platin-pretreated ovarian cancer. Phase I-II study].
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Adult↗
[Importance of platinum dose intensity in treatment of epithelial ovarian cancer. Austrian Study Group for Therapy of Ovarian Cancer].
In a retrospective analysis of 294 patients with FIGO stages III and IV epithelial ovarian cancer treated with different polychemotherapy regimens in two prospective randomised phase III trials between 1981 and 1988, we evaluated the importance of platinum dose intensity for survival. The median survival time of 55 patients who were treated without platinum was 11 months, whereas 205 patients who were treated with a polychemotherapeutic regimen with a platinum dose intensity of 8 mg/m2/week showed a median survival time of 26 months. Of 34 patients who were treated with a platinum dose intensity of 18 mg/m2/week, more than 50% are still alive and therefore the median survival time has not yet been reached (Mantel test p < 0.001). These findings support the hypothesis that an increase in platinum dose intensity during the first treatment regimen leads to an increase in survival of patients with advanced epithelial ovarian cancer. Since 1991 we have been investigating in a prospectively randomized clinical trial whether a combination of carboplatinum and cisplatinum with a planned dose intensity of 43.75 mg/m2/week is feasible and able to improve survival in comparison with standard polychemotherapy (cyclophosphamide/cisplatinum) with a planned dose intensity of 25 mg/m2/week. Evaluation of toxicity of 268 cycles of carboplatinum/cisplatinum in 58 patients showed that a platinum dose intensity of 33.4 mg/m2/week was achievable with acceptable toxicity. Results with regard to therapeutic efficacy of this high dose therapy are expected within the next year.
Adult↗
The differential effects of N,N-dimethylformamide and transforming growth factor-beta 1 on a human ovarian cancer cell line (HOC-7).
We have compared the effects of N,N-dimethylformamide (DMF) and transforming growth factor (TGF)-beta 1 on the growth and phenotype of HOC-7 ovarian cancer cells. Previous density gradient fractionation of untreated HOC-7 cells suggested that rapidly growing small polygonal medium density cells revert spontaneously into less malignant flattened low density cells. Here we demonstrate that DMF and TGF-beta 1 induce similar flattened cell phenotypes. Both agents induce qualitatively similar alterations in the cells. DMF, however, exerted stronger effects than TGF-beta 1. The cells become flattened, develop cytoplasmic extensions, and reduce DNA-synthesis as well as anchorage-dependent and -independent growth. These effects are reversible after removal of the inducers, indicating that the cells have not become terminally differentiated. Electron microscopy demonstrates prominent filament bundles in treated cells. Immunofluorescence further shows that these cells contain large amounts of cytokeratin. Immunocytochemistry and ELISA demonstrate 1- to 5-fold higher amounts of desmoplakin and fibronectin after DMF- or TGF-beta 1-exposure. The described differentiation-like responses of HOC-7 cells can be used for recognition of pharmacologically induced maturation of ovarian cancer cells.
Cell Division↗
Prevalence of antibodies to hepatitis C virus in patients with hepatocellular carcinoma in Austria.
In 12 of 54 (22%) patients with histologically verified hepatocellular carcinoma, antibodies to hepatitis C virus were found. In patients with hepatocellular carcinoma the frequency of anti-hepatitis C virus positivity was similar whether cirrhosis (6 of 22 patients (27%)) was present or not (2 of 15 (13%)). Out of 54, 23 patients (43%) were negative both for hepatitis B or C markers. Out of 53, 22 (42%) had positive hepatitis B markers, 8 of 22 were HBsAg positive. Patients with hepatocellular carcinoma and cirrhosis had a higher percentage of hepatitis B virus markers than patients with cirrhosis without hepatocellular carcinoma. Our of 70 patients with cirrhosis but without hepatocellular carcinoma, 24 (34%) had antibodies to hepatitis C virus. Our data of similar frequencies of antibodies to hepatitis C virus in patients with hepatocellular carcinoma or with liver cirrhosis but without hepatocellular carcinoma indicate that at least in Austrian patients, hepatitis C virus infections are not an important factor for development of hepatocellular carcinoma.
Adolescent↗
Relationship of myc protein expression to the phenotype and to the growth potential of HOC-7 ovarian cancer cells.
In this investigation we demonstrate expression of myc oncoproteins in HOC-7 ovarian adenocarcinoma cells. The cells were exposed to differentiation inducing agents such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), retinoic acid (RA) and transforming growth factor-beta 1 (TGF-beta 1). Myc protein expression in treated cells was then compared with that in control cultures and in monoclonal HOC-7 sublines, which are characterised by distinct phenotypes. Cells exposed to DMSO and DMF became markedly enlarged and flattened and developed cytoplasmic extensions. They looked similar to a subline, which revealed a less malignant and more differentiated cell phenotype. All four inducers prolonged the cell doubling time and reduced the saturation density to levels, normally found in the more differentiated subline. Furthermore, all inducers except RA elevated extracellular fibronectin, which is characteristic for less malignant epithelial cell phenotypes. All four agents inhibited myc oncoprotein expression reversibly (1% DMSO greater than 0.5% DMF greater than 10 microM RA greater than 10 ng ml-1 TGF-beta 1) and in time-dependent manner. Down-regulation of myc protein expression is, therefore, closely related to inducer-dependent growth reduction of HOC-7 cells and to the development of a less malignant cell phenotype.
Actins↗
Comparative analysis of the effects of dimethyl sulfoxide and retinoic acid on the antigenic pattern of human ovarian adenocarcinoma cells.
HOC-7 malignant ovarian surface epithelial cells have been exposed to differentiation promoters like dimethyl sulfoxide (DMSO) and retinoic acid (RA) and the resulting cell phenotypes were characterized immunologically. Immunocytochemistry revealed that DMSO caused elevation of membrane-associated staining for epidermal growth factor-receptor (EGF-R) and for desmoplakins I and II (DPI+II). DMSO also stimulated cytoplasmic and surface labelling for CA 125 and extracellular deposition of fibronectin (FN). A fixed-cell ELISA system was used for quantification of these differentiation-like responses and revealed that DMSO efficiently induced expression of EGF-R, CA 125, FN and DPI+II in dose-dependent manner. Immunocytochemistry, ELISA and Western blotting additionally demonstrated that both DMSO and RA caused down-regulation of myc oncoproteins. Densitometer evaluation of electrophoresed proteins revealed a 50% DMSO- and a 25% RA-induced myc reduction. Apart from growth reduction, which was seen for both inducers, inhibition of myc gene expression was the only response of HOC-7 cells to RA-treatment. The extent of myc down-regulation seems, therefore, to be crucial for the initiation of maturational processes in the cells. Subsequent phenotypic differentiation of HOC-7 cells causes elevated levels of EGF-R, CA 125, FN and DPI+II. This cell model might be useful for the distinction between induced growth reduction and differentiation of ovarian cancer cells.
Adenocarcinoma↗
[Differential prognosis of patients with breast cancer with pleuritis carcinomatosa and with pulmonary lymphangiosis carcinomatosa].
The retrospective analysis of 672 consecutive patients with breast cancer revealed malignant pleural effusion and lymphangitic carcinomatosis of the lung to be the sites of first relapse of the disease in only 2% and 1%, respectively. In half of the 10 patients with malignant pleural effusions evaluable for survival, generalization of the disease was recorded at 51 months (range 0-197 months); the corresponding data for patients with lymphangitic carcinomatosis of the lung (n = 7) were 19 months (range 9-44 months). This difference was statistically significant (p < 0.05). The median survival of patients with pleural effusions and with lymphangitic carcinomatosis of the lung was 22 and 8 months, respectively (n.s.).
Adult↗
Separation of clonogenic and differentiated cell phenotypes of ovarian cancer cells (HOC-7) by discontinuous density gradient centrifugation.
We isolated clonogenic cells from differentiated HOC-7 ovarian cancer cells. Both cell subsets were characterised in respect to morphology, growth behaviour, DNA content and expression of tumour-associated antigens and nuclear oncogenes. Ten cell fractions (Fr) were separated by centrifugation in a discontinuous density gradient (Fr 1 less than 1.037 g/ml to Fr 10 greater than 1.069 g/ml, steps 0.004 g/ml). Large adenoid cells containing vacuoles filled with neutral polysaccharides were concentrated in Fr 1-4. These cells were non-clonogenic in soft agar. The growth on solid substrate was highest in Fr 6 and 7, intermediate in Fr 2-5 and Fr 8-10 and lowest in Fr 1. The mean cloning efficiencies of the fractions in soft agar were highest in Fr 6 (8.1%) and lowest in Fr 2 and 3 (0.1%). Diploid and near tetraploid cell subsets were found with similar frequency in all fractions. Immunocytochemistry revealed 4-7% Ki-67 positive cells in Fr 1-6 and 12-20% in Fr 7-10. In Fr 3-10 greater than or equal to 79% of the cells expressed CA 125. Positivity for c-myc, c-myb and c-fos (greater than or equal to 74%) was not correlated with clonogenicity. In conclusion, differentiated cells (Fr 1-4) were separated from cells with higher growth rates (Fr 5-10). Clonogenic cells were enriched in Fr 6. These data indicate that discontinuous density gradient fractionation represents a useful method for separation of cells with different degrees of differentiation, growth potential and clonogenicity.
Antigens, Tumor-Associated, Carbohydrate↗
Instability of the anticancer agent etoposide under in vitro culture conditions.
Degradation of etoposide is rapid under in vitro culture conditions. At pH 7.4 and 37 degrees C, the isomerisation of trans-etoposide to the inactive compound cis-etoposide has a half-life of 2 days in Dulbecco's modified Eagle's medium and results in the loss of 90% of the active drug within 1 week. As a consequence, prolonged incubations with etoposide in in vitro assays may lead to erroneous interpretations ignoring the real in vitro situation. The degradation is not influenced by organic compounds such as bovine serum albumin or amino acids but depends strongly on the pH value and, to a lesser degree, on the ionic strength of the medium. Therefore, we propose a mathematical correction based on the pH value so as to obtain the real exposure of cells to trans-etoposide during in vitro assays.
Cells, Cultured↗
Phase II study of amonafide in advanced breast cancer.
Twenty-eight patients with advanced breast cancer refractory to prior hormone and/or first-line chemotherapy (with or without anthracycline drugs) were treated with the investigational agent amonafide at a dose of 800 mg/m2 intravenously over 3 hours repeated every 4 weeks. Five objective tumour responses of 5.0 months' median duration were observed in the 20 patients without previous anthracycline exposure, including 1 CR. Leukopenia was the dose-limiting toxicity; though it was generally modest with the 800 mg/m2 amonafide starting dose, an initial dose reduction should be considered in patients with prior radiotherapy and/or bone marrow involvement. Other adverse reactions included nausea/vomiting (53%), phlebitis/erythema along the vein injected (7%), and mild neurotoxic symptoms during the drug administration such as headache, tinnitus, and diaphoresis (21%). Amonafide is an active compound for the treatment of patients with advanced breast cancer and should be considered for further evaluation and incorporation in combination chemotherapy.
Adenine↗
Complete remission of metastasised clear cell sarcoma of tendons and aponeuroses.
Clear cell sarcoma of tendons and aponeuroses is a rare disorder which originates from migrated neural crest cells. It tends to local recurrences and dissemination and the prognosis has to be considered as poor. Based on a small series of patients, a wide surgical excision of the primary tumour or amputation are the therapies of choice. Radiotherapy might be of some value as an adjuvant treatment but radiotherapy and chemotherapy are of little value in the treatment of the advanced disease. Because of the lack of treatment alternatives we treated a 40-year-old female patient with disseminated clear cell sarcoma with interferon-alpha 2b (IFN-alpha 2b) perilesionally after several courses of systemic chemotherapy and radiotherapy had failed. After 4 months of therapy the patient came into a complete pathological remission which lasted for 17 months. A relapse of round cell sarcoma on both tumour sites was then noted. This outcome shows that IFN-alpha 2b was able to induce a complete remission in clear cell sarcoma and might have altered the natural course of the disease. IFN-alpha should be studied as adjuvant therapy after surgery of primary clear cell sarcoma and as a first-line palliative treatment in disseminated disease.
Adult↗
Interferon-alpha induces complete remission in angioimmunoblastic lymphadenopathy (AILD): late development of aplastic anaemia with cytokine abnormalities.
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Anemia, Aplastic↗