14 patients with acute myeloid leukaemia (AML) and 7 with myelodysplastic syndrome (MDS) were treated with cytarabine in low dosage. In AML a complete remission rate of 43% was found and in all patients profound cytopenia was noticed without any sign of maturation induction. In MDS no effect of low-dose cytarabine could be detected. We also studied the effect of low-dose cytarabine in vitro in freshly isolated leukaemic cells of 10 patients with AML. Maturation induction was measured by a comprehensive panel of quantitative and qualitative markers of maturation. No differentiation inducing effect of low-dose cytarabine could be found. We conclude on the basis of our own results and after reviewing the literature that low-dose cytarabine exerts its effect by cytotoxicity instead of maturation induction.
The cytotoxic effects of the bifunctional DNA-reactive drugs cisplatin, mustine and melphalan were studied in two human melanoma cell lines, RPMI 8322 and A 375. A 375 cells were 3.0 times more sensitive to cisplatin and 1.5 times more sensitive to mustine than RPMI 8322 cells. In contrast, A 375 cells were less sensitive to melphalan than RPMI 8322 cells. The increased sensitivity of A 375 cells was parallelled by an increased induction of DNA interstrand crosslinks following exposure to cisplatin and mustine. After cisplatin exposure A 375 cells also showed higher levels of platinum-DNA intrastrand adducts than RPMI 8322 cells. The increased effect of cisplatin in A 375 cells was not due to an increased drug accumulation in these cells. The higher sensitivity of A 375 cells to cisplatin may be related to lower intranuclear levels of glutathione, compared to RPMI 8322 cell nuclei, while the sensitivity to mustine may depend on lower overall levels of glutathione than in RPMI 8322 cells.
The purpose of this study was to compare high-dose chemotherapy (HDCT) with conventional-dose chemotherapy (CDCT) as first-salvage treatment in patients with relapsed or refractory non-seminomatous germ-cell tumors (NSGCT).One hundred and ninety-three patients with relapsed or refractory NSGCT, between 1981 and 1995, were identified from two large databases. In 74 of these, intensification of first-salvage treatment by HDCT was planned. Patients were matched based on primary tumor location, response to first-line treatment, duration of this response and serum levels of the tumor markers, human chorionic gonadotrophin (HCG) and α-fetoprotein (AFP). Multivariate analyses were performed using event-free survival and overall survival as primary endpoints.Full matches on all five factors were found for 38 pairs of patients; for a further 17 pairs, matches on at least four factors could be identified. Hazard ratios in favor of HDCT were obtained between 0.72 and 0.84 [confidence interval (CI) 0.59–1.01] for event-free survival and between 0.77 and 0.83 (CI 0.60–0.99) for overall survival, depending on the type of analysis.The current analysis suggests a benefit from HDCT, with an estimated absolute improvement in event-free survival of between 6 and 12% and in overall survival of between 9 and 11% at 2 years. This benefit is lower than expected from previous phase I/II studies.
Metastatic renal cell carcinoma remains an incurable disease and current modalities can only offer major palliation to a small percentage of patients. Since treatment is palliative, choice and type of therapy must be carefully considered and reconciled with patient desires. When possible, patients should be offered participation in a clinical trial. For patients choosing progestin therapy, treatment with interferon (IFN) or other biological response modifiers can be instituted at the time of progestin failure. Those patients who have slow tumour progression and maintain a high quality of life can be observed without continued progestin therapy. Although pretreatment characteristics predict response to biologicals, no pretreatment characteristic should preclude an individual patient from a trial of IFN therapy. Whether high-dose interleukin-2 (IL-2), IL-2/lymphocyte-activated killer cells, or IL-2/IFN are superior to IFN alone is uncertain, but clinical trials currently underway should help resolve these issues.
Analysis of the fate of the p185HER2 oncoprotein following activation by heregulin β1 revealed the induction of the tyrosine-phosphorylation, down-modulation, and polyubiquitination of p185HER2. Receptor ubiquitination was suppressed in cells treated with heregulin β1 in the presence of sodium azide, an inhibitor of ATP-dependent reactions, or genistein, a tyrosine kinase protein inhibitor, indicating the requirement for kinase activity and ATP in p185HER2 polyubiquitination. Ubiquitinated p185HER2 was degradated by the 26S proteasome proteolytic pathway. Kinetics and inhibition experiments indicated that endocytosis of the receptor occurs downstream of the initiation of the degradation process.
Combinations of dopamine antagonists or high-dose metoclopramide with steroids can provide complete control of chemotherapy-related nausea and vomiting in up to 60–70% of patients undergoing high-dose cisplatin-based chemotherapy. High-dose metoclopramide probably acts as a 5-HT3 receptor antagonist, but because of its dopamine-receptor antagonism it is the cause of extrapyramidal side-effects. These compounds, and the agents used in combination with them, tend to cause sedation, an undesirable effect in the outpatient setting. Specific 5-HT3 receptor antagonists (ondansetron, granisetron, tropisetron) give a similar control of chemotherapy related nausea and vomiting, with minimum side-effects. These drugs can cause headaches and constipation and some have been related to transient liver enzyme abnormalities in cancer patients; however, disease and chemotherapy might also be the cause of the enzyme anomalies. Combinations of 5-HT3 receptor antagonists with steroids may provide a very high degree of protection.
A study of data from 318 cases of uterine sarcoma presenting during a 10-year period (1967-1976) is reported. All but 6 of the patients had at least a 5-year follow-up (98% 5-year follow-up). Overall 5-year survival was 31%, with the major prognostic indicator being tumour stage. Despite the tendency for mixed mesodermal tumours to present in older women with more advanced disease, survival was not statistically different to those patients with leiomyosarcomas. Thus, the propensity for tumour dissemination in leiomyosarcomas should not be underestimated. Leiomyosarcomas are less likely to present with abnormal symptoms than are other sarcomas, and their occurrence as an incidental finding on histological examination underlines the need for an adequate inspection of the intra-abdominal contents at hysterectomy. The tendency to treat all sarcomas as if they were endometrial tumours may be fallacious, and an alternative classification (such as the TNM system) may be required. Recurrence of tumour tended to be at distant sites (distant:pelvic recurrence rate 3:1). Adjuvant radiotherapy is unlikely to alter distant disease foci, and thus the development of combination chemotherapeutic regimens using agents which have shown to result in tumour response seem warranted. Such trials will need to be organised on a multicentre basis to attain statistically evaluable numbers of patients.
A new staging system for multiple myeloma based on clinical and morphological features has been developed on the analysis of 190 patients. A score of "1" was assigned to each of the following clinical data, referred at the time of diagnosis, and selected by multivariate analysis: bone marrow plasma cells more than 30%, haemoglobin less than 110 milligrams, lytic bone lesions of degree 2 or 3, serum beta 2-microglobulin levels higher than 678 nmol/l, and presence of Bence-Jones proteinuria. Therefore, the score for each patient ranged from 0 to 5, and three clinical stages were provided: I = 0 or 1, II = 2 or 3 and III = 4 or 5. Substratification into A and B for each clinical stage was performed using multiple myeloma cellular score, calculated by the formula: total bone marrow myeloma cells per 500 cells x 0.752 + bone marrow plasmablasts per 500 cells x 0.709. Substage A corresponded to multiple myeloma cellular score value lower than 0.300, and substage B to a value greater than 0.300. Significant differences were found in median survivals (P less than 0.0001), in survival curves (P less than 0.0001), and in responses to treatment (P less than 0.0001) among the six staged groups. The use of this staging system for multiple myeloma could offer new prognostic information and could better quantify the picture of the disease in each patient. The substaging according to morphological criteria seems very useful in diminishing or eliminating the great prognostic variability observed within the same clinical stage. Confirmatory studies are required to validate this new staging system for multiple myeloma.
There is a need for assays of DNA damage in many areas of laboratory research applied to radiation therapy, in order to understand the molecular processes involved in cell killing by ionising radiation and to predict in vivo response. Assays exist which measure many types of DNA damage following ionising radiation. From studies of the dose-response relationships for different types of damage, the double-strand break (dsb) has been shown to be the most significant lesion. Assays for DNA dsb have been of low sensitivity, such that supralethal doses of radiation had to be used in order to study dsb induction or repair. New assays, such as pulsed-field gel electrophoresis, are sensitive to dsb in a dose range relevant to cell survival. In addition, these assays can assess the distribution of dsb in different parts of the genome and determine heterogeneity of damage induction and repair. Assays which measure the effects of strand breaks on DNA complexed with nuclear matrix can reveal features of chromatin organisation and their influence on cellular radiosensitivity.
This paper aims to summarize current experience with alpha interferon and provide direction for future study. There are four areas in which alpha interferon has proven or potential activity: antiviral, premalignant, adjuvant and advanced disease settings. The three main viral diseases in which interferon alfa-2b has been shown to have activity are chronic viral hepatitis, acquired immunodeficiency syndrome, and human papilloma virus infections. In vitro studies suggest that alpha interferon may inhibit transformation of some premalignant conditions into malignant disease; e.g., vaginal intraepithelial neoplasia. In the adjuvant setting, it is possible that a biological response modifier, such as alpha interferon, may have a role in helping the immune system to destroy residual tumour cells following tumour bulk reduction with radiation or chemotherapy. A higher response rate has been seen in patients with small tumour bulk compared to those with large tumour bulk (e.g., malignant melanoma, ovarian carcinoma), and in patients with early, rather than late, disease (e.g., chronic myelogenous leukaemia, hairy cell leukaemia, multiple myeloma, non-Hodgkin's lymphoma). This may be due to efficacy in a small tumour bulk setting or due to an immunoadjuvant role. In advanced disease, the question is how best to exploit the possible synergistic effects between alpha interferon and other therapeutic modalities. The optimum dose, schedule and patient populations for combined treatment have yet to be determined. The major objective of this paper is to determine how best to capitalize upon the current state of knowledge to build for future trials of alpha interferon, and to determine whether the existing data suggest an adjuvant role for interferon after initial tumour regression.
Oxidative polymorphism of debrisoquine (DBQ) was assessed in 84 patients (81 male) with histologically proven bronchogenic carcinoma and in 143 healthy male smokers. 80 (95%) patients and 133 (93%) controls, with a metabolic ratio (MR) below 12.6, were classified as extensive metabolisers of DBQ (no significant difference between patients and controls). Only 1 of the 73 patients with epidermoid or microcytic carcinomas was classified as a poor metaboliser (PM) (P = 0.031 compared with controls). 63 patients (75%) and 110 controls (77%) showed a very fast oxidative rate, with MR values under 1 (not significant). The EM phenotype of DBQ might be a secondary genetic risk factor for developing bronchogenic carcinoma in male smokers.
Doxorubicin was encapsulated in small unilamellar thermosensitive liposomes which were strictly defined in terms of size distribution and size stability: more than 95% of vesicles with a maximal diameter of 50 nm stable for a minimum of 24 hours. In addition, the preparation procedure was optimised to achieve the highest differential thermal stability defined as the difference of release between 37° and 43°C exposures in serum-containing medium (dipalmitoylphosphatidylocholine/distearoylphosphatidlylcholine/cholesterol mixture in 5:4:2 molar ratio). The cytotoxicity of thermosensitive-liposome encapsulated doxorubicin was then evaluated in combination with 43°C hypethermia on HelaS3 human tumour cells using colony-forming assays. Results confirmed that hyperthermia potentiates the cytotoxic effects of doxorubicin. Liposome encapsulation was found to further enhance these effects when 0.05 μmol/l doxorubicin concentration was used.
The incidence of head and neck, oesophagus and lung cancer between 1981 and 1985 was studied in Eastern Austria for an urban-rural division. In males, rural rates of oral cavity, oropharynx and oesophagus tumours were higher than urban rates. For lung tumours, urban rates slightly exceeded rural rates. In females, the incidence of oral cavity, oropharynx, larynx, hypopharynx, oesophagus and lung cancer showed an urban predominance, steepest for head and neck and oesophagus cancers. Cancer of the oral cavity, pharynx, larynx, oesophagus and lung had a high male preponderance.
