Pro-oxidative vs antioxidative properties of ascorbic acid in chromium(VI)-induced damage: an in vivo and in vitro approach.

The effect of antioxidant ascorbic acid (vitamin C) pretreatment on chromium(VI)-induced damage was investigated using the yeast Saccharomyces cerevisiae as a model organism. The objective of this study was to pretreat yeast cells with the antioxidant ascorbic acid in an effort to increase cell tolerance against reactive chromium intermediates and reactive oxygen species formed during chromium(VI) reduction. Intracellular oxidation was estimated using the fluorescence indicators dihidro-2,7-dichlorofluorescein, dihydroethidium and dihydrorhodamine 123. The role of ascorbic acid pretreatment on chromium(VI) toxicity was determined by measuring mitotic gene conversion, reverse mutations, 8-OHdG, hydroxyl radical, superoxide anion and chromium(V) formation. The chromium content in the biomass was determined by flame atomic absorption spectrometry. In the absence of chromium, ascorbic acid effectively protected the cells against endogenous reactive oxygen species formed during normal cellular metabolism. In vitro measurements employing EPR and the results of supercoiled DNA cleavage revealed that the pro-oxidative action of ascorbic acid during Cr(VI) reduction was concentration-dependent and that harmful hydroxyl radical and Cr(V) had formed following Cr(VI) reduction. However, the in vivo results highlighted the important role of increased cytosol reduction capacity related to modification of Cr(V) formation, increased chromium accumulation, better scavenging ability of superoxide anions and hydrogen peroxide, and consequently decreased cytotoxicity and genotoxicity in ascorbic acid pretreated cells. Ascorbic acid influenced Cr(VI) toxicity both as a reducing agent, by decreasing Cr(V) persistence, and as an antioxidant, by decreasing intracellular superoxide anion and hydrogen peroxide formation and by quenching free radicals formed during Cr(VI) to Cr(III) reduction. Increased 8-OHdG and decreased reduced glutathione in ascorbic acid-treated cells might induce an endogenous antioxidant defense system and thus increase cell tolerance against subsequent Cr-induced stress.

Prevention of intracellular oxidation in yeast: the role of vitamin E analogue, Trolox (6-hydroxy-2,5,7,8-tetramethylkroman-2-carboxyl acid).

Reactive oxygen species (ROS) are not only generated in conditions of cellular stress but are also constitutively produced in most cell types by specific metabolic processes. This research focused on a potential antioxidant Trolox (model compound for alpha-tocopherol), with the aim to establish exact mechanisms of Trolox intracellular oxidation prevention on model organism Saccharomyces cerevisiae. Measuring intracellular oxidation of Trolox-treated yeast cells revealed that Trolox decreased intracellular oxidation during normal metabolism. Trolox treatment decreased cyto- and geno-toxicity of treated yeast cells in MES buffer, lowered intracellular oxidation, decreased intracellular peroxides formation, and increased H(2)O(2) degradation and superoxide quenching yeast extract ability. This study suggests that Trolox treatment provides prevention against intracellular ROS formation. Trolox application as therapeutic agent against intracellular ROS formation would be worth considering. Additionally, results indicate that yeasts are good model organisms for studying intracellular oxidation and oxidative stress. The obtained results on yeast cells might be useful to direct further human-related search for the Trolox evaluation as a human supplement used for protecting cells against intracellular free radical formation.

Cancer: a reality in the emerging world.

World societies have changed significantly in the last decades. The main characteristics of these changes are reciprocal connections and interdependencies. It has been thus realized that a major part of the world population still lives in poverty. Due to specific health care interventions and consequent demographic changes, it is expected that the population in general, and of the older people in particular, will increase significantly in the future. The annual number of new cases of cancer is expected to double from 10 million at present to 20 million in the next 20 years. Considering the increases in life expectancy and in tobacco abuse worldwide, and the existence of viral diseases leading to cancer in less developed countries besides other factors, the majority of new cases will probably occur in the emerging world. The number of new cases of cancer could in the future be reduced with the enhancement of education on vertical and horizontal levels in less developed countries. On the vertical arm, the education would concentrate on physicians, nurses, and other health care workers, while on the horizontal arm, it would be provided to government officials, politicians, and other decision-makers. It should be accepted that the world is one and that the problems associated with cancer in less developed countries are global problems. Semin Oncol 28:210-216.

Electric treatment of human melanoma skin lesions with low level direct electric current: an assessment of clinical experience following a preliminary study in five patients.

In this study we have investigated the effects of negative low level direct electric current electrotherapy (current: 1 milliampere; treatment time: 30 minutes) in metastatic or primary melanoma skin lesions. After 12 applications in five patients, tumour regression was observed in all evaluable melanoma skin lesions; four of them were classified as partial responses. This study shows that locally applied electrotherapy with a negative low level direct electric current is an effective treatment that results in reduction of tumour mass of human melanoma skin lesions, and it is possible that it has a positive influence on the course of the metastatically disseminated melanoma. No serious side effects were observed.

The course of metastatic disease originating from carcinoma of the prostate.

The purpose of this work was to study the time sequence and the patterns of the multistep spread of metastases. Fifty-one patients with stage D carcinoma of the prostate, previously treated for their primary tumor by surgery or radiotherapy combined with hormonal manipulation and for metastases by hormones and chemotherapy, were included in the study. The metastatic dissemination, characterized primarily by the appearance of bone metastases, could follow two distinct patterns: The first, characterized by sequential appearance of osteoblastic metastases, followed by the development of osteolytic bone lesions, and the second pattern, characterized by the simultaneous appearance of osteoblastic and osteolytic bone lesions. In cases with solely osteoblastic bone metastases, the lesions are hormone sensitive and long-lasting remissions could be obtained. The development of osteolytic bone lesions is usually accompanied by the recurrence of the primary tumor and appearance of metastases in other sites, such as the lymph nodes and lungs. Bone metastases became resistant to hormonal manipulation and with chemotherapy short remissions were obtained. The course of the terminal period is faster, with shorter survival times. The determination of serum acid and alkaline phosphatase levels seems to reflect the course of the disease during the initial period of the disease only, i.e. when bone metastases are sensitive to hormonal treatment.

Combined BCG and irradiation treatment of skin metastases originating from malignant melanoma.

Treatment with BCG (Bacillus Calmette-Guérin) followed by irradiation was attempted to improve response to therapy by cutaneous metastases from malignant skin melanomas. Both agents were applied in low doses, known to cause minimal side effects. Nineteen patients, divided into three groups, entered the clinical trial. The first group consisted of five patients with relatively large metastases that usually appeared as a residual disease in the surgically treated area. Five patients with numerous, large metastases were included in the third group. The treatment sequence consisted of applying BCG intralesionally in doses from 4 x 10(5) to 1.17 x 10(7) viable units. After a free interval, the affected area was irradiated with doses from 1500--2500 ret. Patients with numerous small metastases and those with a small number of larger metastases, i.e., patients of the first and second group, showed a complete response and in these cases regression affected all the noninjected nodules and was also effective when regression could not have been achieved by BCG alone.

The growth of primary subcutaneous fibrosarcoma and its pulmonary metastases in normal and athymic Swiss mice.

The growth of primary subcutaneous fibrosarcomas and their pulmonary metastases was studied in normal and athymic Swiss mice. The metastases tended to develop more rapidly than did the primary tumors. However, when growth rates of tumors of small volumes (up to 1 cm3) were compared, the tumor and metastases exhibited similar rates of development in both strains indicating the growth rate of pulmonary metastases was related to that of the tumor of origin. Modified immune reactivity, as in athymic mice, influenced the growth of the same tumor in that the subcutaneous fibrosarcoma exhibited a faster rate of development, while the growth rate of pulmonary metastases decreased, when compared with growth in Swiss mice. Therefore, it appears that growth characteristics of the primary tumor from which metastases originated and the reactivity of the host must be included among the factors determining metastatic growth rates.

Chemotherapy of disseminated malignant melanoma with imidazol carboxamide (DTIC) and cyclophosphamide. Preliminary results.

Forty three patients with disseminated malignant melanoma were treated by combination chemotherapy with DTIC (800 mg/m2) and subsequent peroral cyclophosphamide (100 mg/m2) for 14 days. Overall response was observed in 18/43 (42%), and complete response in 9/43 (21%) cases. Complete response was achieved mainly in patients with metastatic involvement of lungs. Mean survival from onset of treatment for responding patients was significantly longer than mean survival of nonresponders (15 versus 5 months, respectively). Serious complications were not noted.

Serum immunoglobulin levels and survival rates in bronchogenic carcinoma patients.

Serum immunoglobulin IgG, IgA and IgM levels were estimated in 112 patients with bronchogenic carcinoma, and the obtained values were as follows: IgG = 1762 +/- 595 mg/100 ml; IgA = 332 +/- 104 mg/100 ml; IgM = 157 +/- 76 mg/100 ml. Subsequently the patients were divided in a group of 74 patients with epidermoid carcinoma, and a group of 38 patients with small cell anaplastic carcinoma of the bronchus. In patients with epidermoid carcinoma, in cases with disseminated disease the mean survival was shorter (7.9 months) when compared to the mean survival of patients with localized disease (20.8 months). Similarly, a depression of lymphocyte counts was observed in cases with disseminated disease. In cases with IgA concentrations ranging from 300 to 410 mg/100 ml longer survival rates were observed. In patients with small cell anaplastic carcinoma variety, the survival rates in patients with localized disease were almost identical with those in patients with disseminated disease (11.4 months versus 9.9 months). The longest survival rates were observed in cases with IgG concentrations ranging from 1600 to 2100 mg/100 ml, and IgM concentrations ranging from 190 to 320 mg/100 ml of serum.

Actual volume doubling time values for pulmonary metastases from soft tissue sarcomas.

Doubling time values of pulmonary metastases from soft tissue sarcomas were measured. Sixty metastases from 24 patients were measured 79 consecutive times, and, the values for 116 doubling times were calculated. Small volume metastases grew significantly faster (arithmetic mean 29.7 days) than large metastases (arithmetic mean 43.4 days). An assessment with comparative data obtained previously by measuring the doubling time values of pulmonary metastases from osteogenic sarcoma revealed similar growth characteristics. The possible involvment of identical control mechanisms operating in the growth process of pulmonary metastases in both soft tissues and osteogenic sarcomas are discussed.

Actual doubling time values of pulmonary metastases from malignant melanoma.

The growth rate of pulmonary metastases was determined in 18 patients with pulmonary metastases from histologically proven malignant melanoma. From chest radiograms 81 metastases were measured 51 consecutive times, and 120 values for doubling time were obtained. metastases with diameters of 15.0 mm or less grew significantly faster (arithmetic mean=24.9 days) than metastases with diameters over 15.0 mm (arithmetic mean=51.0 days). The difference is statistically significant (P less than 0.050). In about one-tenth (9.2%) of all measurements the values for doubling time are considerably lengthened (arithmetic mean=182.2 days). The determination of doubling time values may be considered as a useful parameter in the selection of patients for treatment of pulmonary metastases from malignant melanoma.

Prognostic significance of skin reactivity in patients with bronchogenic carcinoma grouped according to the TNM classification.

Untreated patients with bronchogenic carcinoma of the epidermoid type showed a marked depression of cutaneous delayed hypersensitivity reactions to DNCB, PPD and Varidase. As compared to a control group of healthy individuals and to a control group of patients with non-malignant chest diseases, 46% of cases responded to the DNCB skin test, 56% to the PPD skin test and 39% to the Varidase skin test. The patients were subsequently divided according to the TNM classification in stage I, II and III groups. Correlation of the skin test positivity to the stage of the disease and to the survival of patients was followed.

L-Asparaginase: effect on 7S gamma globulin extents and germinal centers in spleen and lymph-nodes.

Administration of L-asparaginase may cause remission in a high percentage of acute lymphocytic leukemias and lymphomas, either in experimental animals or in human beings. This enzyme is able to depress immune reactions like lymphocyte blastogenesis and delayed hypersensitivity, and to impair gamma-globulin synthesis. L-asparaginase also has antigenic properties, and may cause the formation of anti-L-asparaginase antibodies. This study reports observations on the effect of L-asparginase on the 7S gamma-globulin levels and on the behaviour of the germinal centers in spleen and lymph nodes. It has been found that after administration of low or intermediate doses of L-asparginase, a decrease in the size of the follicular marginal zones occurred. This was accompanied by an enlargement of the germinal centers. Furthermore the spleen weight decreased and the concentration of 7S gamma-globulin diminished slightly. In animals given high doses of L-asparaginase, germinal centers were enlarged even more but marginal zones appeared repopulated although not to the degree of the controls. The spleen weight of these enzyme-injected animals reached almost the normal values, while a statistically significant decrease of 7S gamma-globulin concentrations was found.

Abdominal lymphoma with alpha-heavy chain disease.

Clinical, immunochemical and pathological studies were performed in a 27-year-old male who presented with abdominal pain, the malabsorption syndrome, and marked weight loss. Immunoelectrophoretic studies revealed alpha-heavy chains in the patient's serum, urine and intestinal juice. Treatment with cyclophosphamide and corticosteroids produced an improvement in the patient's condition and he survived for 18 months after the onset of symptoms. Autopsy revealed a malignant lymphoma of mixed histiocytic-lymphocytic type involving mainly the mesenteric lymph nodes, but also affecting the jejunal mucosa, liver, spleen and extraabdominal lymph nodes. This is the first case of abdominal lymphoma with alpha-heavy chain disease to be reported from Yugoslavia.