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Biomedical subjects

A J Veerman

Publications and source records attributed to A J Veerman.

At least 19 recordsLinked to original sources
PubMed1992

Hypoxanthine-guanine phosphoribosyl-transferase in childhood leukemia: relation with immunophenotype, in vitro drug resistance and clinical prognosis.

Decreased activity of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT), responsible for the conversion of 6-mercaptopurine and 6-thioguanine (6-TG) to their cytotoxic nucleotides, may cause resistance to these thiopurines in experimental leukemic systems. The clinical significance of this mechanism is as yet unclear. In 83 children with untreated acute lymphoblastic leukemia (ALL), we determined the prognostic value of HGPRT activity and the relation between HGPRT activity and resistance to thiopurines. HGPRT activity was determined radiochemically; in vitro resistance to 6-TG with the MTT assay. HGPRT level was significantly lower in T-ALL than in B-lineage ALL; no differences were found between sequential differentiation stages of B-lineage ALL. HGPRT activity was inversely related to the white-blood-cell count (WBC). Among patients with cALL and pre-B-ALL with WBC less than 50 x 10(9)/l, cases with a low HGPRT had a significantly poorer prognosis than those with a high HGPRT. WBC, age, sex, organomegaly and differentiation stage were comparable in both patient groups. No correlation was found between HGPRT activity and in vitro 6-TG resistance in cALL and pre-B-ALL patients. T-ALL cases were not more 6-TG-resistant than cALL and pre-B-ALL cases. Cells from 6 relapsed ALL cases did not show decreased HGPRT activity. We conclude that: (a) HGPRT is lower in T- than in B-lineage ALL and is constant in sequential differentiation stages of B-lineage ALL; (b) HGPRT activity is inversely related to tumor load; (c) low HGPRT activities are correlated with a poorer prognosis in precursor B-ALL but this cannot be explained by thiopurine resistance because (d) there is no relation between HGPRT activity and in vitro 6-TG resistance.

Adolescent↗
PubMed1992

Relation of 5'-nucleotidase and phosphatase activities with immunophenotype, drug resistance and clinical prognosis in childhood leukemia.

Ecto-5'-nucleotidase (ecto-5'NT) catalyzes the extracellular dephosphorylation of nucleotides like IMP. Cytoplasmic 5'NT (cyto-5'NT) and non-specific (e.g. acid- and alkaline) phosphatases (AP) regulate the intracellular degradation of nucleotides. High NT and AP activities might cause a resistance to the thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). We studied the relation between these enzymes and immunophenotype, drug resistance and prognosis in 77 children with acute lymphoblastic leukemia (ALL). Enzyme activities were assessed radiochemically; in vitro drug resistance was measured with the MTT assay. AP activities were higher in T-ALL and B-ALL than in precursor B-ALL. Cyto-5'NT activity was very low in all phenotypes and accounted for a significant proportion of total IMPase activity only in the very immature CD10- c mu- precursor B-ALL. CD10+ ALL cases with high ecto-5'NT activities showed a trend (p = 0.065) for a lower probability of continuous complete remission than those with a low activity. Ecto-5'NT activity was not related to in vitro drug resistance to 6-TG. A weak correlation was found between in vitro 6-TG resistance and cyto-5'NT and AP activities. We conclude that high ecto-5'NT activities do not cause a resistance to 6-thiopurines in childhood ALL. Some patients have high cyto-5'NT and AP activities associated with 6-thiopurine resistance.

5'-Nucleotidase↗
PubMed1992

Different types of non-P-glycoprotein mediated multiple drug resistance in children with relapsed acute lymphoblastic leukaemia.

Although cellular drug resistance is considered to be an important cause of the poor prognosis of children with relapsed acute lymphoblastic leukaemia (ALL), the knowledge of drug resistance in these patients is very limited. Different aspects of drug resistance were studied in 17 children with relapsed ALL. The in vitro sensitivity profile was determined using the MTT assay. Cells from relapsed children were significantly more resistant to 6-thioguanine, prednisolone, cytosine arabinoside, daunorubicin (DNR), mustine-HCl and mafosfamide but not to L-asparaginase and vincristine (VCR) than cells from 41 children with ALL at initial diagnosis. Some relapsed patients showed a general drug resistance while others were resistant to only 1-3 drugs. The relevance of the multidrug resistance (MDR) model was analysed: In all DNR- and VCR resistant cases a co-resistance to drugs not involved in the MDR model was found. P-glycoprotein was not detected in any of 28 untreated and 14 relapsed samples tested. VCR- and DNR accumulation in the most resistant cells were not lower than in sensitive cells. Resistance modifiers did not potentiate the cytotoxicity of VCR and DNR. We conclude that resistance to anthracyclines and vinca alkaloids in childhood relapsed ALL is not due to P-glycoprotein mediated MDR. Different types of drug resistance varying from a resistance to only one drug to a general chemoresistance, can be detected in children with relapsed ALL. VCR and L-asparaginase seemed to be only infrequently involved in drug resistance. Knowledge of drug resistance might lead to more effective and less toxic therapies for children with relapsed ALL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

[Growth hormone therapy and leukemia].

In this literature study the possible correlation between GH-therapy and leukemia has been critically evaluated. Two central questions have been studied: 'does leukemia occur more often in GH-deficient children in GH-therapy than in age-related normal individuals' and 'which influences of GH administration upon normal and leukemic leukocytes have been described?'. In some cases leukemia developed in GH-deficient children after GH-therapy. The data have shown a higher incidence of leukemia in the population of children treated with GH (5:100,000) than in the age-related normal population of children (2:100,000). However, hard evidence supporting the hypothesis that GH-therapy could induce leukemia has not yet been found. In vivo studies could not detect enhanced growth of blood cells influenced by GH-therapy. In vitro studies showed that GH either stimulated or did not affect the proliferation of unstimulated lymphocytes of GH-deficient children, normal individuals or leukemia-patients. The same effects occurred in leukemic cell lines. On PHA-stimulated lymphocytes of GH-deficient children and normal individuals both enhancing and inhibiting effects of GH have been found. It is suggested that GH-therapy could improve immunological resistance against tumors by improving Natural-Killer-cell activity. In mice GH seemed to influence lymphocyte-differentiation. In mice also an increase in the frequency of chromosomal aberrations related to GH has been observed. This evaluation suggests that patients, treated with GH-therapy should be carefully followed up. Also, the indication for GH-therapy has to be guarded critically.

Adolescent↗
PubMed1992

Adenosine deaminase and purine nucleoside phosphorylase in childhood lymphoblastic leukemia: relation with differentiation stage, in vitro drug resistance and clinical prognosis.

Many reports have described the relationship of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) activities with the immunological subclasses of acute lymphoblastic leukemia (ALL). The clinical significance of these enzymes in leukemias is not yet completely understood. We performed a study in 83 children with untreated ALL to establish the relationships of ADA and PNP to clinical outcome, in vitro drug resistance and differentiation stage of B-cell lineage ALL. ADA and PNP activities were determined radiochemically. In vitro resistance to 6-thioguanine (6-TG) was determined with the MTT assay. ADA activity was not different between proB- and cALL cases but decreased in the sequential differentiation stages cALL----preB-ALL----B-ALL. The PNP level was not different between the four stages of B-lineage ALL. Patients with cALL/preB ALL with low ADA activities had a significantly poorer probability of survival (p = 0.005) than patients with high ADA levels. Patients with cALL/preB ALL with low PNP activities showed a non-significant trend for a poorer prognosis (0.05 less than p less than 0.10) than patients with a high PNP level. Low ADA and PNP activities were not related to in vitro resistance to 6-TG. We conclude that ADA decreases and PNP remains constant in sequential differentiation stages of B-lineage ALL. Patients with precursor B-lineage ALL with low activities of ADA have a poorer prognosis than those with high activities of these enzymes. No relationship could be detected between ADA or PNP activity and resistance to 6-TG.

Adenosine Deaminase↗
PubMed1991

Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia.

The clinical relevance of cellular drug resistance in children with acute lymphoblastic leukaemia (ALL) is unknown. The relation between in-vitro sensitivity to chemotherapeutic drugs at initial diagnosis and long-term clinical outcome was investigated in 44 children with ALL. The short-term MTT assay was used to assess sensitivity to prednisolone, vincristine, colaspase (asparaginase), daunorubicin, and thioguanine (instead of mercaptopurine which is unstable in vitro). For vincristine and colaspase there was no difference in outcome (probability of continuous complete remission) between sensitive and resistant patients. However, the probability of continuous complete remission was significantly lower in patients with resistant cells than in those with sensitive cells for thioguanine (p less than 0.01), daunorubicin (p less than 0.02), and prednisolone (p less than 0.05). For prednisolone there was a significant worsening of the prognosis (p less than 0.05) from the extremely sensitive patients through an intermediate group to the most resistant group. The prognostic significance of cellular drug resistance was independent of white-blood-cell count, age, sex, and hepatosplenomegaly. Leukaemic cells from boys were more resistant to thioguanine than those from girls. Thus, the short-term highly efficient MTT assay can help to predict long-term response to chemotherapy in childhood ALL.

Antineoplastic Agents↗
PubMed1991

Primary spinal epidural extraosseous Ewing's sarcoma.

The case of a 7-year-old boy with a spinal epidural extraosseous Ewing's sarcoma (EES) is presented. He is in complete remission without neurologic deficit 40 months after diagnosis. Another 15 cases were found in the literature and are discussed together with this patient. Twelve of them were male patients. The mean age of the patients was 17.5 years (range, 4 to 47). Symptoms included back pain and/or radicular pain (100%), paresis of one or both legs (83%), sensory disturbances, and bladder and bowel dysfunction. The mean diagnostic delay was 5.8 months. Each patient underwent laminectomy; complete resection of the tumor was impossible in more than 50% of the cases. Most patients received radiation therapy and/or chemotherapy. Four patients suffered from local recurrence, eight from metastases. Ten (63%) patients died, 1 to 48 months (mean, 16) after diagnosis. The differential diagnosis is discussed, including disk herniation and several benign and malignant tumors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Expression of 5'-nucleotidase (CD73) related to other differentiation antigens in leukemias of B-cell lineage.

Ecto-5'nucleotidase (5'NT; CD73) expression was studied with a monoclonal antibody (7G2) and a radiochemical assay and compared with the expression of other antigens in B-cell-lineage leukemias on cells from 100 leukemic patients and two cell lines. A B-cell origin was confirmed by the expression of CD19 and HLA-DR. Four stages of B-cell leukemias were defined: stage I (pro-B) as CD10-, cytoplasmic mu- (c mu-), surface Ig- (sIg-); stage II (cALL) as CD10+/c mu-/sIg-; stage III (pre-B) as CD10+ or -/c mu+/sIg-; and stage IV (B) as CD10-/c mu-/sIg+. A linear correlation was found between immunohistochemical and radiochemical determination of 5'NT (r = .86). 5'NT expression was low in T-cell leukemias and stage I, high in stages II and III, and low again in stage IV of B-cell leukemias. 5'NT expression was not related to c mu, CD20, CD21, CD22, CD34, and terminal deoxynucleotidyl transferase (TdT) expression, but was significantly related to CD10 and inversely related to kappa/lambda expression. However, the 5'NT activity in CD10+ leukemias (stages II and III) shows a very wide range. Within the group of CD10+ leukemias no differences were detected between 5'NT+ and 5'NT- cells in their expression of other B-cell antigens. We conclude that the place of 5'NT in leukemias corresponding to early stages of B-cell development has been characterized. 5'NT is expressed in CD10+ stages and decreases before the expression of sIgs. Future studies should make clear whether a high expression of this enzyme in CD10+ stages is a normal maturation phenomenon or a malignant phenomenon.

5'-Nucleotidase↗
PubMed1991

In vitro drug sensitivity of normal peripheral blood lymphocytes and childhood leukaemic cells from bone marrow and peripheral blood.

In vitro drug sensitivity of leukaemic cells might be influenced by the contamination of such a sample with non-malignant cells and the sample source. To study this, sensitivity of normal peripheral blood (PB) lymphocytes to a number of cytostatic drugs was assessed with the MTT assay. We compared this sensitivity with the drug sensitivity of leukaemic cells of 38 children with acute lymphoblastic leukaemia. We also studied a possible differential sensitivity of leukaemic cells from bone marrow (BM) and PB. The following drugs were used: Prednisolone, dexamethasone, 6-mercaptopurine, 6-thioguanine, cytosine arabinoside, vincristine, vindesine, daunorubicin, doxorubicin, mafosfamide (Maf), 4-hydroperoxy-ifosfamide, teniposide, mitoxantrone, L-asparaginase, methotrexate and mustine. Normal PB lymphocytes were significantly more resistant to all drugs tested, except to Maf. Leukaemic BM and PB cells from 38 patients (unpaired samples) showed no significant differences in sensitivity to any of the drugs. Moreover, in 11 of 12 children with acute leukaemia of whom we investigated simultaneously obtained BM and PB (paired samples), their leukaemic BM and PB cells showed comparable drug sensitivity profiles. In one patient the BM cells were more sensitive to most drugs than those from the PB, but the actual differences in sensitivity were small. We conclude that the contamination of a leukaemic sample with normal PB lymphocytes will influence the results of the MTT assay. The source of the leukaemic sample, BM or PB, does not significantly influence the assay results.

Adult↗
PubMed1991

Differentiation dependent expression of P-glycoprotein in the normal and neoplastic human kidney.

Adult renal cell carcinoma (RCC) is clinically resistant to chemotherapy. However, in nephroblastoma (NBL) chemotherapy has increased survival dramatically. We studied the P-glycoprotein (P-gp) expression of 18 RCC and 9 NBL as well as 1 benign renal adenoma and fetal renal tissue using three different monoclonal antibodies (MRK-16, C-219, JSB-1). P-gp was found positive with all three antibodies in 12/18 RCC, while only 2 tumors were completely negative. Staining varied with respect to intensity and number of positive cells [5%-90%]. Intense staining was seen at the apical side of malignant tubules in well differentiated parts of RCC and in tubular structures of the benign renal adenoma. Poorly differentiated parts of the tumors showed less staining. In NBL blastemal parts were negative. In 4/8 specimens showing focal epithelial differentiation, however, the luminal side of more differentiated tubular structures did stain, strongly resembling P-gp staining in the developing fetal human kidney. These results indicate that P-gp expression in normal (fetal) human kidney as well as in benign and malignant tumors derived from this organ depends on the degree of differentiation of tubules, which may have implications for chemotherapy sensitivity in both malignant tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Cytotoxic effects of vitamin A in combination with vincristine, daunorubicin and 6-thioguanine upon cells from lymphoblastic leukemic patients.

We studied whether isotretinoin potentiated the effects of vincristine (VCR), daunorubicin (DNR), and 6-thioguanine (6-TG) against cells obtained from 24 patients with acute lymphoblastic leukemia (ALL). Treatment with 5 micrograms/ml isotretinoin alone resulted in a leukemic cell survival of 82% +/- 28.1%. So isotretinoin is toxic to ALL cells. Dose-response curves were obtained for VCR, DNR and 6-TG in the presence and absence of isotretinoin Isotretinoin showed additive leukemic cell kills in combination with VCR and DNR. When corrected for cell kill by isotretinoin alone, it appeared that isotretinoin did not significantly enhance leukemic cell kills by VCR, DNR and 6-TG. No differences were found between samples from patients at initial diagnosis and at relapse with respect to cell kill by isotretinoin alone and with respect to a possible synergistic effect of isotretinoin and the cytostatic drugs. It is concluded that isotretinoin has additive antileukemic effects in combination with VCR or DNR. However, isotretinoin does not potentiate the antileukemic effects of VCR, DNR and 6-TG against leukemic cells obtained from patients with ALL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Function and morphology of respiratory cilia in situs inversus.

The activity and ultrastructure of respiratory cilia were studied in 13 individuals with situs inversus but without serious respiratory complaints, in 8 patients with Kartagener's syndrome and in 50 healthy controls without situs inversus. In 3 individuals with situs inversus abnormal ciliary activity was found, comparable in every aspect to the ciliary activity in patients with Kartagener's syndrome. In 4 individuals with situs inversus a dynein arm deficiency was present in the cilia, with abnormal ciliary activity in 3 of them. The number of outer dynein arms per cilium differed significantly between the 3 groups (P less than 0.02). Apparently, situs inversus without serious respiratory complaints can be associated with primary ciliary dyskinesia. Based on the findings in this study, the incidence of primary ciliary dyskinesia in the Caucasian population appears to be 1:12,500.

Adolescent↗
PubMed1991

Diagnosis of Wiskott-Aldrich syndrome by analysis of the X chromosome inactivation patterns in maternal leucocyte populations using the hypervariable DXS255 locus.

The Wiskott-Aldrich syndrome (WAS) is characterized by severe recurrent infections, petachiae and chronic eczema. The syndrome involves differentiation disorders in several haematopoietic cell lineages usually manifested as T lymphocyte deficiency, dysgammaglobulinaemia and thrombocytopenia. The defect is inherited in an X-linked recessive mode. A 1-year-old boy presented with otitis, upper respiratory infections, eczema, a persistent granulocytopenia and a dysgammaglobulinaemia. In his family five males in two generations had been shown to have WAS, which entailed a significant risk for the patient to have WAS. As the WAS gene or gene product is not delineated, the symptoms of the patient presented a diagnostic dilemma. If the boy had inherited the disease, his mother should be a WAS carrier. Segregation analysis in the family using the closely linked restriction fragment length polymorphisms (RFLP) DXS7, DXS255 and DXS14 did not exclude her carriership, although the probability was low. As a result of the differentiation arrest, obligate female WAS carriers manifest a unilateral X chromosome inactivation pattern in several haematopoietic cell lineages. Methylation analysis of the X chromosomal DXS255 loci exposed random X chromosome inactivation patterns in the peripheral blood granulocytes, T lymphocytes and B lymphocytes of the patient's mother. These findings excluded her WAS carriership and therefore excluded the diagnosis of WAS in the patient. This was further substantiated in a 1-year follow up with recovery from the haematological and immunological symptoms. These results demonstrated that X inactivation analysis in maternal leucocytes is decisive in the exclusion of the diagnosis of WAS.

Blotting, Southern↗
PubMed1991

[Pearson's syndrome: a multi-system disorder based on a mt-DNA deletion].

In 1979 Pearson described a syndrome, in which the main symptoms were severe sideroblastic anemia and exocrine pancreas dysfunction. The aetiology was still unknown. A decade later, the Pearson syndrome can be described as a lethal multisystem disorder, in which the bone marrow and exocrine pancreas show major dysfunction, but also other organs (like kidneys, liver, gut and skin) can be affected. These patients also show growth retardation. The study of the mitochondrial DNA allowed identification of a deletion in the mitochondrial DNA. The case of a patient suffering from Pearson's syndrome is reported.

Acidosis, Lactic↗
PubMed1990

In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions.

The knowledge about drug resistance in childhood leukemias and acute lymphoblastic leukemia (ALL) in general is limited. This is because of the lack of a suitable in vitro drug sensitivity assay, which is in part due to low in vitro ALL cell survival. We recently adapted the highly efficient 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay to test cells from ALL patients and showed that its results were comparable with those of the DiSC assay, up to now the most valid but laborious assay. In this study, in vitro drug sensitivity was assessed in cells from 82 children with leukemia, 79 of whom had ALL, with the MTT assay. Dose response curves were obtained for 6-mercaptopurine, 6-thioguanine (6-TG), prednisolone (Pred), daunorubicin (DNR), vincristine (VCR), cytosine arabinoside (Ara-C), L-asparaginase (L-Asp), mafosfamide, and mustine. A cytotoxic effect of methotrexate could be detected in only a few cases. Large interindividual differences in drug sensitivity were detected. Compared with leukemia cells from newly diagnosed patients, leukemia cells from relapsed patients were significantly more in vitro resistant to 6-TG, Pred, Ara-C, mafosfamide and mustine but not to DNR, VCR, and L-Asp. Improvements of culture medium and methods to increase MTT reduction were studied. From 10 components tested, addition of insulin and bovine serum albumin to serum-containing medium improved ALL cell survival. Addition of succinate did not increase the amount of MTT reduction. We conclude that the in vitro MTT assay highly facilitates large-scale studies on drug resistance of ALL patients that can lead to rational improvements in existing treatment protocols.

Asparaginase↗
PubMed1990

Diagnosis of pyruvate kinase deficiency in a transfusion-dependent patient with severe hemolytic anemia.

In a 2-yr old girl a hemolytic anemia was present since birth requiring multiple blood transfusions. Pyruvate kinase deficiency was suspected on the basis of a marginal enzyme activity, but could not be established due to the presence of massive numbers of donor cells in her peripheral blood. However, by density fractionation we succeeded in the isolation of a small fraction of the patient's own cells, in which a severe pyruvate kinase deficiency could be detected. In contrast hexokinase and glucose-6-phosphate dehydrogenase activities were extremely high, which is indicative that a very immature cell population is present in this fraction. In immunofluorescence studies a clear crossreaction was apparent with anti M2-type pyruvate kinase antibodies, whereas only a faint reaction with anti L-type could be detected. Despite the presence of a slight amount of L-type immunoreactive material, the residual activity in the patient's cell fraction could only be attributed to M2-type pyruvate kinase as was shown by cellulose acetate electrophoresis.

Anemia, Hemolytic↗