ISSN:0378-584X    

DOI:10.1159/000218856

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

ISSN:0378-584X    

DOI:10.1159/000218857

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

The division cycle of normal mammalian cells is governed by a highly coordinated network of interacting mechanisms that ensure a correct succession of the biochemical and biophysical events culminating in mitosis. A family of specific protein kinases, the Cdks, constitute the motor element of cell cycle progression. Their function is regulated at several levels: 1. association with a cyclin subunit situates their activity in different phases of the cell cycle; 2. sequential phosphorylation and dephosphorylation on specific amino acid residues is required for their final activation; 3. their activity can be modulated by complexing with members of the cyclin-dependent kinase inhibitor family (Cdkls). The latter function to a large extent as effectors of signals emitted by cell surface receptors or internal sensors of defective biochemical and biophysical states termed checkpoints. While the fate of cells is largely influenced by external factors throughout Gl phase, an intrinsic program becomes responsible for cell cycle progression after the passage of the ‘restriction point’ at the Gl/S boundary. This crucial transition is controlled by a checkpoint mechanism in which the concerted action of p53 and the retinoblastoma protein may induce either a cell cycle arrest or apoptosis in response to genomic damage. Several other checkpoint functions regulate the entry into mitosis by assessing the completion of DNA replication and correct chromosome attachment to the spindle apparatus. Finally, the number of possible cell divisions is predetermined by the number of small oligonucleotide repeats at the utmost chromosome ends, the telomeres. Checkpoint mechanisms can be disrupted by viral oncoproteins or gene mutations. Loss of their function is likely to result in genomic destabili-zation and gene amplification, which again may allow for chromosome aberrations and, as several connections link the genome to the cell cycle machinery, may permit unrestrained cell growth. The majority of the cell cycle-related proteins, however, do not qualify for monitoring the prolifer-ative activity or the tumor growth fraction. To date, only three proteins: p345 (Ki-67), pl70 (topoisomerase II-alpha), and p100 (S-phase protein) have been identified as selective indicators of cellular proliferation. The first two recognize all cell cycle phases except GO, whereas the latter is specifically expressed in S, G2, and M phase cells. Application of antibodies to these proteins in clinical pathology was found to be highly relevant for the prediction of tumor biology and clinical cour

ISSN:0378-584X    

DOI:10.1159/000218858

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

The methods commonly used to detect MDRl/P-glycoprotein (Pgp) in patients’ tumors differ widely in sensitivity and specificity and are not standardized. This seems one reason for the often discrepant results reported on the incidence and clinical relevance of MDRl/Pgp expression in particular tumor types. Recently, an international workshop was conducted which had the goal to standardize MDRl/Pgp detection methods for future clinical studies. Good interlaboratory agreement was found in the detection of high level MDRl/Pgp expression, whereas considerable variation was observed in the detection of low expression levels as typically found in patients’ tumors. Detection was more reliable in leukemias than in solid tumors. RT-PCR showed the highest sensitivity. In leukemias, flow cytometry was more sensitive than immunostaining in detecting Pgp, and analysis of Pgp function was more sensitive than detection of Pgp expression. Major recommendations for future studies were: Assay conditions and reagents need to be properly calibrated. With each assay, the use of appropriate negative and positive controls is crucial. RT-PCR assays need to be performed in the exponential range of amplification. For immunohistochemistry, at least two anti-Pgp antibodies should be used which recognize distinct epitopes. For flow cytometry, antibodies should be preferred which recognize external epitopes, and functional Pgp assays should be performed in the absence versus presence of Pgp-blocking agents. Functional assays should be accompanied by analyses of MDRl/Pgp expression. Multiparameter analyses are encouraged whenever possi

ISSN:0378-584X    

DOI:10.1159/000218859

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Patients with superficial transitional cell carcinoma of the bladder (Ta, Tl, Tis) can nowadays be subdivided in different risk groups for tumor recurrence and progression, based on prognostic factors, which have been obtained from the results of clinical Phase III trials. For adjuvant therapy a choice can be made between intravesical instillations with chemotherapeutic or immunotherapeutic agents. The optimal treatment schedule and time to start intravesical therapy is not known. None of the investigated chemotherapeutic agents turned out to be superior in delaying tumor recurrence. Intravesical immunotherapy, using bacillus Calmette Guérin (BCG), seems to be as effective and maybe superior in high-risk groups in delaying tumor recurrence compared to chemotherapeutic agents. The side effects, however, are a disadvantage. The exact working mechanism of BCG and its antitumor effect is not known. In the field of recognizing patients at risk for recurrence or progressive disease, biological markers have been identified. In daily practice these markers cannot be used yet. Using all these different treatment options, it is important to obtain information on the impact of these treatment schedules on the quality of life, especially if the treatment results do not differ. A start has been made to imply questionnaires in superficial bladder cancer studies

ISSN:0378-584X    

DOI:10.1159/000218860

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Background: To study the toxicity and pharmacokinetics of LU103793 (Cematodin®), a novel cytotoxic anticancer drug being an analogue of Dolastin 15 which was isolated originally from the Indian Ocean sea hare Dolabella auricularia. Method: 9 patients with refractory metastatic solid tumors were treated in a phase I study. The drug was administered as rapid (5 min) intravenous bolus injection at 3-weekly intervals. 14 courses of LU103793 were totally administered. The starting dose was 2.5 mg/m2 and escalated to 20 mg/m2 within 4 steps. Results: The dose-limiting toxicity was a) reversible hypertension, and b) cardiac infarction. No significant myelotoxicity was observed. Other toxicities were nausea and vomiting, drug fever, pain at the tumor site and asthenia. Concentrations of LU103793 and its main metabolite were measured in all 9 patients in whole blood samples. Two exponential terms are necessary to describe the c(t) profile. The pharmacokinetic parameters at 20 mg/m2 are: maximum concentration 9.0 ± 7.2 μM, the area under the curve 37.3 ± 6.8 μM × h, the plasma clearance 0.8+0.14 1/hour/m2, the volume of distribution at steady state 9.6 ± 2.0 1/m2 and the elimination half-life 10.3 ± 1.5 h. The AUC was increasing from 4.6 μM × h at 2.5 mg/m2 dose level to 37.3 μM x h at 20 mg/m2 dose level, suggesting a linear kinetic in the range of the tested doses. No objective tumor regression was observed. Conclusions: The dose-limiting toxicity (DLT) was reached at 20 mg/m2 with cardiovascular side-effects. Hypertension and a myocardial infarction determined the DLT. The mechanism of the observed cardiovascular side effect is still unclear. In case that high peak blood levels are critical with respect to the observed toxicity, prolongation of the drug administration either as continuous infusion or a split mode (repetitive drug application over 3-5 days) should avoid this problem. Phase I trials with such application modes are i

ISSN:0378-584X    

DOI:10.1159/000218861

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Background: Doxorubicin and ifosfamide are the most active drugs in the treatment of adult advanced soft tissue sarcoma. For patients not or no longer responding to these cytostatic agents no widely accepted salvage chemotherapy is known. Patients and Methods: Between 1986 and 1995 100 adult patients with advanced soft tissue sarcoma were treated with a combination of doxorubicin and ifosfamide. After transient response or primary failure to this combination, salvage chemotherapy was administered to 22 patients. 14 patients were treated with dacarbazine (DTIC) 1,200 mg/m2 as a 20-min infusion every 3 weeks, and 8 patients received a combination of carboplatin 300 mg/m2 as a 1-hour infusion on days 1 and 2 and VP-16 300 mg/m2 as a 1-hour infusion on days 1 and 2 every 3 weeks. Results: Treatment with DTIC led to stable disease in 2 patients and progressive disease in 12 patients. The combination of carboplatin/VP-16 resulted in stable disease in 1 patient and progressive disease in 7 patients. Overall, no remission was seen in 22 patients. Conclusions: Although the number of patients treated by us was small, neither DTIC nor carboplatin/VP-16 seem to be effective salvage chemotherapy regimens in adult patients with advanced soft tissue sarcoma pretreated with doxorubicin/ifosfamide.

ISSN:0378-584X    

DOI:10.1159/000218862

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Background: This investigation is done to evaluate the extent of β-Interferon-induced radiosensitization and the underlying mechanisms by which β-Interferon alters the radiation response of two different human tumours in vitro. Material and Methods: Two human tumors were studied in vitro. One was the second passage of a human squamous cell carcinoma of the head and neck (ZMK-1), the other was the breast cancer cell line MCF-7. Cells were cultured by standard methods. β-Interferon was used in concentrations from 10 to 1,000 IE/ml medium, incubation times were 3 h (pulse) or for the remainder of the incubation for colony formation (continuous). Cells were either attached to their flasks or in suspension. The cells were irradiated with 200-kV X-rays at dose levels from 2 to 10 Gy. Evaluation was done by colony assay. Results: For MCF-7 cells we found an antiproliferative effect caused by β-Interferon depending on concentrations and incubation times. When combined with X-radiation we found no additional effects of β-Interferon for both kinds of cells irradiated in suspension. When the cells were irradiated attached to their flasks, β-Interferon caused a slight radiosensibilization with respect to the MCF-7 cells and a pronounced effect with respect to the ZMK-1 cells, the isoeffect enhancement ratio being 1.5, determined at the 10% survival level. Conclusion: These results demonstrate that under the influence of β-Interferon repair of sublethal radiation damage of MCF-7 and ZMK-1 cells is decreased by a short preirradiation incubation time. Additionally, lethal radiation of ZMK-1 cells is increased by β-Int

ISSN:0378-584X    

DOI:10.1159/000218863

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Background: Manifold metastatic spread of renal cell carcinoma, even after long-term latency, is feared and unpredictable. Late recurrence after more than 10 years is not rare and then often initially misdiagnosed. Patient and Material: We are reporting on a 76-year-old male patient in whom an axillary lymph node metastasis was diagnosed 20 years after tumor nephrectomy and preoperative radiotherapy for a renal cell carcinoma. After tumor extirpation and 6 cycles of interferon therapy axillary failure recurred. Due to unexplained upper abdominal symptoms, an abdominal CT was carried out and a tentative diagnosis of a local recurrence in the former renal bed was made. Laparotomy was necessary due to a blocked passage resulting from a duodenal stenosis. Results: A local recurrence with compression of the duodenum was histologically confirmed. A duo-denojejunostomy was carried out for passage reconstruction. Conclusions: Regular follow-up care is particularly important for patients with renal cell carcinomas, since isolated late metastases can occur after 20 years or more. However, the diagnosis is often delayed, since a malignant disease originating from the primary is not expected after such a long interval. With aggressive therapy for those late recurrences/metastases, some patients can still survive for years depending on their general condition.

ISSN:0378-584X    

DOI:10.1159/000218864

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger

摘要:

Background: Interferon-alpha (IFN-alpha) and retinoic acid have been found to be active agents in the treatment of squamous-cell carcinomas. Recent experimental and clinical studies indicate an improvement of treatment results, if this agents are combined with irradiation. Material and Method: We report about a 53-year-old patient presenting with an advanced non-small-cell lung cancer. Systemical treatment with IFN-alpha and 13-cis retinoic acid was performed concurrently with radiotherapy. The patient’s follow-up, response and toxicity of this therapeutic regimen were evaluated. Result and Conclusions: The combination of IFN-alpha/retinoic acid with irradiation seems to be effective in the management of advanced non-small-cell carcinomas of the lung. However, in rare cases combined treatment with IFN-alpha and radiotherapy may be associated with increased side effects, especially radiation pneumoniti

ISSN:0378-584X    

DOI:10.1159/000218865

出版商:S. Karger GmbH    

年代:1996

数据来源: Karger