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S Vitols

Publications and source records attributed to S Vitols.

At least 37 records · Page 2Linked to original sources
PubMed1995

Multidrug resistance (Mdr1) gene expression in peripheral blasts from patients with acute leukemia only rarely increases during disease progression after combination chemotherapy.

Multidrug resistance gene (mdr1) RNA levels were determined in 55, and P-glycoprotein expression in 37 samples of peripheral leukemic cells from 17 patients with acute myeloblastic leukemia (AML) and 7 patients with acute lymphocytic leukemia (ALL). Between sample collections, patients were treated with various chemotherapy regimens. Mdr1 RNA levels were quantified by a RNA-RNA solution hybridization assay. P-glycoprotein was determined by Western blot analysis. Samples from 14 patients (9 AML, 5 ALL) had undetectable mdr1 RNA levels at initial analysis. Only two of these had detectable levels after chemotherapy. Ten patients (8 AML, 2 ALL) had detectable mdr1 RNA levels at initial analysis (median 1.0 transcript per cell, range 0.2-1.4). Increase of mdr1 RNA levels after chemotherapy were observed in cells from 3 patients, one patient had a lower level after chemotherapy and the 6 remaining patients had essentially unchanged mdr1 RNA levels in their leukemic cells. Samples from 13 patients were sequentially analysed for P-glycoprotein expression. In one patient, no P-glycoprotein was detectable at initial analysis but was weakly positive after chemotherapy. In the remaining 12 patients, P-glycoprotein levels stayed stable during disease progression. In conclusion, combination chemotherapy seems only rarely to be associated with an increase of mdr1 gene expression in residual leukemic cells. The addition of resistance modifiers to chemotherapy in order to overcome P-glycoprotein mediated resistance might therefore be more effective in chemotherapy naive patients since it is possible that during later disease progression additional mechanisms of resistance may be more operative.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Multilevel regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in normal and leukemic cells.

Altered cholesterol homeostasis has been noted in malignant cells, which led us to explore the regulation of cholesterol metabolism in normal and leukemic cells. The mean low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities were fivefold and threefold higher in mononuclear blood cells from 33 patients with leukemia, compared with cells from 23 healthy subjects, whereas elevations in RNA levels were twofold and 40% only. The activities of the two proteins correlated in normal cells (r = .46), whereas an inverse correlation was found in leukemic cells (r = -.40). Relatively weak correlations were found between LDL receptor RNA levels and receptor activity in normal (r = .48) and leukemic cells (r = .49), and HMG-CoA reductase RNA levels correlated (r = .53) with reductase activity in leukemic cells only. The ratios of protein activities to RNA levels in cells were constant during consecutive blood samplings and similar in leukemic blood and bone marrow cells from the same individual. During cholesterol deprivation, protein activities increased more than RNA levels, and leukemic cells with high LDL receptor activity showed a partial resistance to the suppressing effect of sterols on LDL receptor gene expression. The results demonstrate that LDL receptor RNA levels alone can not explain variation in receptor activity, suggesting post-RNA regulation of LDL receptor expression, similar to what has been described for HMG-CoA reductase. Taken together, the present results suggest multilevel regulation of both proteins and demonstrate that each cell clone, normal or malignant, has a unique ratio of protein activity to RNA level. Leukemic cells, in contrast to normal cells, can meet increased cholesterol requirements by either elevated LDL receptor activity or increased cholesterol synthesis, which is of potential interest for diagnosis and specific treatment of leukemia.

Adult↗
PubMed1993

Effect of verapamil on daunorubicin accumulation in human leukemic cells with different levels of MDR1 gene expression.

The purpose of the present study was to evaluate the distribution of the multiple drug resistance phenotype in leukemic cells with different levels of mdr1 gene expression. Peripheral leukemic cells from 8 patients (5 with detectable and 3 with undetectable mdr1 RNA levels) were incubated with daunorubicin (1 microM) in the absence and presence of verapamil (6.6 microM). Daunorubicin accumulation in individual cells was analysed by flow cytometry. Verapamil increased (16-45%) the mean daunorubicin accumulation in 7 of the 8 cell samples. In cells from 4 of these 7 patients, the fluorescence histograms showed a general increase of daunorubicin accumulation. The increase was limited to a small subpopulation of cells in one patient. In the remaining two patients an increase of daunorubicin accumulation was seen in the majority of cells, while cells with the highest accumulation were unaffected. In conclusion, verapamil can increase daunorubicin accumulation in leukemic cells with and without detectable mdr1 gene expression and the increase seems to affect the majority of the cell population.

Adult↗
PubMed1992

Elevated uptake of low density lipoproteins by human lung cancer tissue in vivo.

In order to explore new treatment modalities for cancer, it is important to identify qualitative or quantitative differences in metabolic processes between normal and malignant cells. Previous in vitro and in vivo studies have shown that acute myelogenous leukemia cells have elevated receptor-mediated uptake of low density lipoproteins (LDL), compared to normal WBC. High receptor-mediated uptake of LDL by certain cancer cells in tissue culture and experimental tumors in animals in vivo has also been demonstrated. The present study was undertaken to compare the in vivo assimilation of LDL by human lung cancer tissue with that by surrounding lung tissue. Ten patients with newly diagnosed lung tumors, scheduled for surgery, received an i.v. injection of [14C]sucrose-labeled LDL. Following cellular uptake and degradation of the LDL particle, the radiolabeled sucrose moiety remains trapped in the lysosomal compartment, making this labeling technique useful for in vivo studies of tissue uptake of LDL. Radioactivity was determined in plasma and in tissue biopsies obtained at surgery 1-3 days after injection. The uptake of radioactivity in lung cancer tissue was elevated (1.5-3.0-fold), compared to surrounding tissue, in 7 of 9 patients with primary lung cancer. The most rapid preoperative disappearance of radioactivity from plasma was found in 2 patients with large tumors exhibiting high LDL uptake, relative to normal lung tissue. These findings support the hypothesis that the selectivity of cytotoxic agents can be enhanced also in nonhematological malignancies by administering the drugs incorporated in LDL particles.

Adult↗
PubMed1992

Quantitative determination of mdr1 gene expression in leukaemic cells from patients with acute leukaemia.

By using a quantitative RNA-RNA solution hybridisation method, the average number of mdr1 RNA transcripts per cell was measured in total nucleic acid extracts of leukaemic cells from patients with acute leukaemia. The results in different types of leukaemia were (number of patients with detectable mdr1 RNA/total number of patients; median number of transcripts per cell in samples with detectable mdr1 RNA); de novo untreated acute myelocytic leukaemia (AML): 20/44; 0.7, secondary acute myelocytic leukaemia: 8/13; 1.1, acute lymphocytic (ALL) and undifferentiated leukaemia: 5/14; 0.6, relapsed leukaemia: 7/15; 0.7. Forty-six patients with de novo untreated acute leukaemia (AML: n = 34, ALL: n = 12) were evaluable for response to induction chemotherapy. Twelve of 18 patients (67%) with detectable mdr1 RNA levels achieved complete remission compared to 23 of 28 (82%) with undetectable levels (P = 0.40). The remission duration tended to be longer among patients with undetectable mdr1 RNA (P = 0.08). Leukaemic cells were analysed on consecutive occasions in 12 patients. The level of expression increased in four and decreased in two. In conclusion, expression of mdr1 RNA is common in acute untreated leukaemia. However, treatment with cytostatic drugs seems only rarely to increase the proportion of leukaemic cells that express mdr1 RNA. Expression of the mdr1 gene could be one of several equally important factors contributing to drug resistance in acute leukaemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Influence of age on the metabolism of plasma low density lipoproteins in healthy males.

The plasma concentration of the atherogenic low density lipoproteins (LDL) increases with age. To clarify the mechanism of this change, we studied the kinetics of autologous 125I-LDL apolipoprotein B (apo B) in 41 normolipidemic, nonobese healthy males. For comparison, they were divided into three age groups: young, 21-39 yr (n = 18), middle-aged, 40-59 yr (n = 11), and old, 60-80 yr (n = 12). The levels of plasma LDL cholesterol and LDL apo B increased from respectively 3.4 +/- 0.1 (SEM) mmol/liter and 86 +/- 2 mg/dl in the young to 4.1 +/- 0.1 mmol/liter and 95 +/- 3 mg/dl in the old (P less than 0.01), and this increase was linked to a progressively decreased (r = -0.38, P less than 0.02) fractional catabolic rate of LDL apo B (0.348 +/- 0.010 pools per day in the young vs. 0.296 +/- 0.009 pools per day in the old, P less than 0.01). The production rate of LDL apo B did not differ significantly between the groups. The reduced fractional catabolic rate of LDL apo B in the old was not associated with a decrease in binding affinity of the LDL particle to its receptor, as judged from its ability to compete for 125I-LDL fibroblast binding. When hepatic LDL receptor expression was stimulated by cholestyramine treatment in six old males, their LDL apo B fractional catabolic rate increased to the levels observed in the young subjects. We conclude that the increase in LDL which normally occurs with age is explained by a reduced capacity for its removal, and hypothesize that this is mediated via a reduced hepatic LDL receptor expression.

Adult↗
PubMed1991

Uptake of low-density lipoprotein by malignant cells--possible therapeutic applications.

Cells acquire cholesterol via de novo synthesis and receptor-mediated uptake of low-density lipoprotein (LDL), the major cholesterol-carrying lipoprotein in blood. Human leukemic cells and certain tumor tissues display elevated receptor-mediated uptake of LDL as compared with the corresponding normal cells or tissues. LDL has therefore been proposed as a potential carrier for chemotherapeutic agents. Various methods have been employed to incorporate antineoplastic lipophilic drugs into LDL, and the resultant drug-LDL complexes have been shown to be cytotoxic toward tumor cells in vitro. Initial experiments with tumor-bearing animals suggest that LDL may be a promising carrier for drugs in the treatment of malignant diseases.

Animals↗
PubMed1990

Low density lipoprotein for delivery of a water-insoluble alkylating agent to malignant cells. In vitro and in vivo studies of a drug-lipoprotein complex.

Previous studies have shown that human leukaemic cells and certain tumour tissues have a higher receptor-mediated uptake of low density lipoprotein (LDL) than the corresponding normal cells or tissues. LDL has therefore been proposed as a carrier for anti-cancer agents. In the current study, a water-insoluble mitoclomine derivative (WB 4291) was incorporated into LDL. The WB 4291-LDL complex contained about 1,500 drug molecules per LDL particle and showed receptor-mediated toxicity in vitro as judged from the difference in growth inhibitory effect on normal and mutant (LDL-receptor-negative) cultured Chinese hamster ovary cells. However, cellular drug uptake did not exclusively occur by the receptor pathway since mutant cells were also affected to some extent. The LDL part of the complex had the same plasma clearance and organ distribution as native LDL after i.v. injection in mice and rabbits. Therapeutic effects were observed when Balb-C mice with experimental leukaemia were treated with the complex. After i.p. administration to mice with i.p. leukaemia median survival time was prolonged 2.5-fold and 40% became long time survivors. The effect was weaker (42% increase in life span) after i.v. injections of the complex to mice with i.v. leukaemia.

Alkylating Agents↗
PubMed1990

Uptake of low density lipoproteins by human leukemic cells in vivo: relation to plasma lipoprotein levels and possible relevance for selective chemotherapy.

The success of cancer chemotherapy is dependent on the possibility to utilize biological differences between malignant and normal cells to selectively destroy the tumor cells. One such difference may be that of receptor-mediated cellular uptake of low density lipoproteins (LDLs). Previous studies have shown that leukemic cells from patients with acute myelogenous leukemia have elevated receptor-mediated uptake and degradation rates of plasma LDL in vitro compared to normal white blood and bone marrow cells, and that plasma cholesterol levels at diagnosis are inversely correlated with the LDL receptor activity of the malignant cells. An important question is whether the uptake of LDL by the leukemic cells is also increased in vivo. To evaluate the in vivo uptake of LDL, 11 adult patients with newly diagnosed acute myelogenous leukemia received an i.v. injection of [14C]-sucrose-labeled LDL. On degradation of [14C]sucrose-LDL, the radiolabeled sucrose moiety is known to remain trapped in the lysosomal compartment of the cells. After injection, radioactivity accumulated progressively for at least 12 hr in the leukemic cells. The uptake of radioactivity in vivo correlated with the rate of receptor-mediated degradation of 125I-labeled LDL by the leukemic cells assayed in vitro (r = +0.88, P less than 0.001). An inverse correlation between plasma LDL cholesterol concentrations and the in vivo cellular uptake of [14C]sucrose-LDL in whole blood (r = -0.76, P less than 0.01) indicates that the hypocholesterolemia is due to elevated LDL uptake by the leukemic cells. Postmortem biopsies from virtually all tissues were obtained from one patient, and the distribution of radioactivity revealed that the liver and bone marrow had accumulated most radioactivity; the adrenals had the highest uptake of label per gram of tissue weight. The results indicate that LDL may be used as a carrier targeting lipophilic cytotoxic drugs to leukemic cells.

Adult↗
PubMed1988

Impaired low-density lipoprotein receptor activity in chronic B-lymphocytic leukaemia cells.

Cellular degradation of 125I-labelled low-density lipoprotein (LDL) was analysed in freshly isolated blood mononuclear cells from 26 patients with chronic B-lymphocytic leukaemia (CLL) and 8 healthy subjects, and in cells following 1, 2 and 3 d of culture in medium containing 10% human lipoprotein-deficient serum (LPDS). Fresh CLL cells had lower LDL degradation rates than mononuclear cells from healthy subjects (p less than 0.01). The LDL degradation rates increased during culture (p less than 0.001), but to a lesser degree in CLL cells than in normal blood mononuclear cells (p less than 0.001). The cellular degradation rate of 125I-LDL was markedly inhibited by an excess of unlabelled LDL, indicating that most of the 125I-LDL that was degraded had been internalized following binding to the high-affinity cell surface receptor. There was a positive correlation between the LPDS-induced LDL degradation of CLL cells and the thymidine uptake in CLL cell cultures with (r = 0.70, p less than 0.001) and without (r = 0.59, p less than 0.01) the B cell mitogen, Epstein-Barr virus. The results indicate that LDL receptors might be involved in the regulation of CLL cell proliferation.

Aged↗
PubMed1986

Low-density lipoprotein as a carrier of antitumoral drugs: in vivo fate of drug-human low-density lipoprotein complexes in mice.

Previous studies have demonstrated that human leukemic cells and certain cancer cells in culture have a higher uptake of plasma low-density lipoprotein (LDL) than the corresponding normal cells. Therefore LDL has been proposed as a drug carrier for anticancer agents. In the present investigation, we have developed a method to incorporate a lipophilic derivative of doxorubicin, N-trifluoroacetyladriamycin-14-valerate, into LDL. The method involves lyophilization of LDL in the presence of sucrose as protective agent and gives an N-trifluoroacetyladriamycin-14-valerate-LDL complex containing about 100 drug molecules per LDL particle. The in vivo fate of the complex in mice as judged from the disappearance from plasma and accumulation in organs was similar to that of native LDL. When cultured human fibroblasts were incubated with N-trifluoroacetyladriamycin-14-valerate-LDL, cellular drug accumulation was dependent on the LDL receptor activity of the cells. The covalent linkage of two anthracycline derivatives to lysine residues of LDL yielded conjugates with drug/LDL molar ratios ranging up to 80. With increasing substitution, there was a progressive decline in the affinity of the conjugate for the LDL receptor in vitro. The in vivo fate of such conjugates was quite similar to that of native LDL. We conclude that it is possible to associate cytotoxic agents with LDL without interfering with its in vivo behavior.

Animals↗
PubMed1985

Hypocholesterolaemia in malignancy due to elevated low-density-lipoprotein-receptor activity in tumour cells: evidence from studies in patients with leukaemia.

59 patients with acute leukaemia were examined to see if hypocholesterolaemia, which is commonly found in acute leukaemia, was due to the high low-density-lipoprotein (LDL)-receptor activity of leukaemic cells. LDL-receptor activity was found to be inversely correlated with plasma-cholesterol concentration. Patients with both a high LDL-receptor activity per cell and a high white-blood-cell count had the lowest cholesterol concentrations. During chemotherapy, cholesterol levels rose concomitantly with the disappearance from the peripheral blood of leukaemic cells. Hypocholesterolaemia in leukaemia and other neoplastic disorders may be due to increased LDL-receptor activity in the malignant cells. This high uptake and degradation of LDL by malignant cells could be utilised to target neoplastic cells with LDL-bound chemotherapeutic agents.

Adolescent↗
PubMed1985

Hypocholesterolemia in cancer patients may be caused by elevated LDL receptor activities in malignant cells.

Several epidemiological studies indicate an inverse relation between plasma cholesterol and the occurrence of cancer. Since we in previous studies have found that certain malignant cell types have an elevated LDL receptor activity, the aim of the present study was to further explore the possibility that an elevated LDL consumption by tumor cells causes hypocholesterolemia. The plasma cholesterol concentrations in patients with acute leukemia were inversely correlated with the rate of receptor-mediated degradation of 125I-LDL by the leukemic cells. During chemotherapy, the total plasma and the LDL cholesterol levels increased concomitantly with the reduction in the leukemic cell count in a patient whose leukemic cells exhibited a high rate at receptor-mediated degradation of 125I-LDL. In certain patients with inoperable urinary bladder carcinoma, the plasma cholesterol concentration fell as the disease progressed. Studies in breast cancer patients indicate that the number of LDL receptors in the tumor tissue may have prognostic significance. The results are in agreement with the hypothesis that an elevated LDL receptor activity in malignant cells may lead to hypocholesterolemia.

Blood Donors↗
PubMed1985

Low density lipoprotein receptor activity in human leukemic cells--relation to chromosome aberrations.

Chromosome analysis and low density lipoprotein (LDL) receptor activity of leukemic cells from 38 patients with acute non-lymphocytic leukemia were correlated. Clonal chromosome aberrations were found in 22 patients, and an extra chromosome 8 was found in 7 of them. LDL receptor activity was significantly higher in patients with an extra chromosome 8 than in patients with other abnormalities or a normal karyotype. Chromosome 8 may harbor genes of importance for the expression of the LDL receptor.

Adolescent↗