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Biomedical subjects

A T Look

Publications and source records attributed to A T Look.

At least 199 records · Page 11Linked to original sources
PubMed1983

Macrophage-mediated cytostatic activity blocks lymphoblast cell cycle progression independently in both G1 phase and S phase.

Recent work has shown that macrophage-mediated cytostatic activity inhibits cell cycle traverse in G1 and/or S phase of the cell cycle without affecting late S, G2, or M phases. The present report is directed at distinguishing between such cytostatic effects on G1 phase or S phase using the accumulation of DNA polymerase alpha as a marker of G1 to S phase transition. Quiescent lymphocytes stimulated with concanavalin A undergo a semisynchronous progression from G0 to G1 to S phase with a dramatic increase in DNA polymerase alpha activity between 20 and 30 hr after stimulation. This increase in enzyme activity was inhibited, as was the accumulation of DNA, when such cells were cocultured with activated murine peritoneal macrophages during this time interval. However, if mitogen-stimulated lymphocytes were enriched for S-phase cells by centrifugal elutriation and cocultured with activated macrophages for 4-6 hr, DNA synthesis was inhibited but the already elevated DNA-polymerase activity was unaffected. Similar results were obtained when a virally transformed lymphoma cell line was substituted as the target cell in this assay. These results show that both G1 and S phase of the cycle are inhibited and suggest that inhibition of progression through the different phases may be accomplished by at least two distinct mechanisms.

Animals↗
PubMed1983

Effects of the epipodophyllotoxin VP-16-213 on cell cycle traverse, DNA synthesis, and DNA strand size in cultures of human leukemic lymphoblasts.

Serial studies of human leukemic lymphoblasts (CCRF-CEM line) cultured with 0.25 to 2.5 microM VP-16-213 for 0 to 6 hr indicated that the mechanism of cytotoxicity of this compound involves a primary effect on DNA. The most striking early change shown by flow cytometry in VP-16-213-treated cells was a delay in S-phase transit before arrest of cells in G2. Coinciding with this S-phase delay was a selective inhibition of thymidine incorporation into DNA as well as concentration-dependent scission of DNA strands. Using alkaline elution methods, we were able to detect DNA breakage at concentrations of VP-16-213 well below the level required to demonstrate kinetic effects or inhibition of DNA synthesis. These data suggest that DNA strand scission is the initial event in the sequence of kinetic and biosynthetic changes leading to growth inhibition and death of VP-16-213-treated cells. Inhibition of replicon initiation due to strand scission is a plausible explanation for the cytotoxic action of this podophyllotoxin derivative.

Cell Cycle↗
PubMed1983

Comparative cytotoxic and cytokinetic effects of the epipodophyllotoxins 4'-demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-beta-D-glucopyranoside) and 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-beta-D-glucopyranoside) and their metabolites on human leukemic lymphoblasts.

We compared the effects of the epipodophyllotoxins 4'-demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-beta-D-glucopyranoside) (VP-16-213) and 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-beta-D-glucopyranoside) (VM-26) and several of their derivatives on cell cycle progression and viability of human leukemic lymphoblasts (CCRF-CEM). The cis-(picro)-lactone derivatives, like both VP-16-213 and VM-26, produced G2-phase arrest and cytotoxicity, but only at concentrations 100 times greater than required with the parent compounds. The epiaglycone derivative showed potent cytotoxicity: at 100 to 250 nM, it reduced cloning efficiency by 50%, an effect requiring 25 to 40 nM VM-26 and 340 to 425 nM VP-16-213. In contrast to VM-26 and VP-16-213, the epiaglycone arrested cells in M, consistent with evidence that it, like podophyllotoxin, is an inhibitor of microtubule assembly. At concentrations resulting in 50% cell kill and an increase of cells in M, however, the epiaglycone produced little change in the proportion of cells in G1 or early S phase, while podophyllotoxin produced a shift of cells to mid- and late S. The hydroxy acid derivatives, although found in detectable quantities in patients' urine and serum, were inactive in vitro. Structural differences among the compounds account for their different biochemical and cell kinetic effects and, hence, different cytotoxic activities. Because the epiaglycone is a potent compound and combines activities of both the podophyllotoxins and 4'-demethyl derivatives, further studies of its cytotoxicity are indicated.

Cell Cycle↗
PubMed1982

Acute lymphocytic leukemia: biological markers of clinical response.

Treatment for acute lymphocytic leukemia (ALL) has been successful in producing cures for some children with that disease. It has become increasingly important therefore to develop treatment regimens for curable All that are effective for disease control but carry minimal risks of late detrimental consequences. For other children current therapy is still inadequate and treatment failure occurs. For these children current altered treatment strategy must be developed that includes intensification of some treatment components, since improved methods of disease control are the primary consideration. In this paper the clinical and laboratory methods by which risk groups can be defined at diagnosis have been described. We have increasingly effective means by which the expected treatment outcome with current therapy can be defined at diagnosis. This assignment to a specific risk group is important to provide children with ALL with the most appropriate therapy for their expected clinical response. These studies of clinical utility also pose biological questions concerning the relationship to such things as white blood count, leukemic cell karyotype, and initial proliferative activity to the likelihood of drug resistance emerging. During the coming decade there will no doubt be an increasing emphasis on a biological characterization of leukemic cell populations. Answers must be developed to such questions as the mechanism for leukemic cell growth regulation. Biological information developed in this model tumor cell system in humans will likely produce information of value in understanding human cancer in general.

Aneuploidy↗
PubMed1982

Pharmacokinetics of Teniposide (VM26) and etoposide (VP16-213) in children with cancer.

The clinical pharmacokinetics of VM26 and VP16-213 were assessed in 15 children (median age 10 years) with acute leukemia, using a new high-performance liquid chromatography-electrochemical assay. Pharmacokinetic parameters were calculated by both model-dependent and compartment model-independent methods. These studies demonstrated substantial differences in the central volumes of distribution (VDc), steady-state volumes of distribution (VDss) and systemic clearances (Cls) of VM26 and VP16-213; with the VDc, VDss, and Cls all being smaller for VM26, Systemic clearances determined by model-independent methods were 5.2 +/- 1.0 ml/min/m2 (mean +/- SD) for VM26 and 17.8 +/- 11.2 ml/min/m2 for VP16-213. The major metabolites. detected in serum and urine were the hydroxy acids. Low levels of the picro-lactone isomers were detected in some patients while the aglycones were not detected in the serum or urine of any patients.

Biotransformation↗
PubMed1982

Cytokinetically based induction chemotherapy and splenectomy for childhood acute nonlymphocytic leukemia.

A four-drug regimen, based on cell kinetic principles, induced complete remissions in 68 of 95 children (72%) with acute nonlymphocytic leukemia (ANLL). Patients entered remission after 2-5 weekly cycles of vincristine-daunorubicin (day 1) followed by sequential cytosine arabinoside and 6-azauridine (days 4-7). With continuation therapy of monthly vincristine-doxorubicin-cyclophosphamide, weekly cytosine arabinoside, and daily 6-mercaptopurine, the median duration of complete remission was 10 mo and the median survival time 21 mo. Portal triaditis, evident in 11 of 23 patients with liver biopsies, was associated with long remissions. A larger spleen size (greater than 5 cm) and a higher myeloblast labeling index (greater than 10%) at diagnosis were clearly related to shorter durations of remission. Splenectomy within 1 mo of remission had no statistically significant effect on the frequency of relapse or length of remission. Patients without central nervous system (CNS) leukemia at diagnosis, all treated prophylactically with intrathecal methotrexate, had a low frequency of initial CNS relapse (3/56, 5%). The 2-yr disease-free survival rate is 29% (20 of 68 patients attaining complete remission). fifteen patients have completed 2.5 yr of therapy, and each remains in continuous complete remission, off treatment, for 1+ -36+ mo. This induction chemotherapy was as effective as more intensive regimens, with the advantage of less toxicity and shorter periods of hospitalization.

Acute Disease↗
PubMed1982

Prognostic importance of chromosome number in 136 untreated children with acute lymphoblastic leukemia.

Leukemia cell karyotypes were determined at diagnosis for 136 of 159 consecutive patients with acute lymphoblastic leukemia (ALL) who were followed for up to 35 mo. Ninety patients (67%) had abnormal karyotypes. Five chromosome categories were designated, based on the distribution of modal numbers: hyperdiploid greater than 50 (n = 41), hyperdiploid 47-50 (n = 18), pseudodiploid (n = 28), normal (n = 46), and hypodiploid (n = 3). Treatment response was assessed for the categories in terms of time to failure (induction failure, first relapse, or death). Children in the hyperdiploid greater than 50 category had the best responses to treatment, with only 2 failures, and those in the pseudodiploid category had the poorest (p less than 0.001). The remaining 3 chromosome categories had intermediate responses and formed a third prognostic group. This same influence of chromosome number on time to failure was evident within the 2 clinical prognostic groups: high risk, signified by a leukocyte count greater than 100 X 10(9)/liter, meningeal leukemia, mediastinal mass, or the presence of blasts that formed rosettes with sheep erythrocytes at 37 degrees C, and standard risk, indicated by the absence of these features. The influence of chromosome number on time to failure was also the same within the historically favorable prognostic group that had common ALL. Results of a multivariate analysis indicated that chromosome number was the strongest single predictor of outcome (p less than 0.001) and was the only variable that added significant prognostic information to leukocyte count (p less than 0.001). The combination of chromosome number and leukocyte count should more clearly distinguish patients with ALL at low or high risk of relapse.

Asparaginase↗
PubMed1982

Aneuploidy and percentage of S-phase cells determined by flow cytometry correlate with cell phenotype in childhood acute leukemia.

Cellular DNA content distributions of propidium-iodide-stained bone marrow blasts were determined by flow cytometry (FCM) for 225 untreated children with acute leukemia and were correlated with leukemia cell phenotype and karyotype. Aneuploidy of the primary malignant stem line was detected in 54 cases (24%): 51 hyperdiploid and 3 hypodiploid. A second stem line with approximately twice the DNA content of the primary stem line was recognized by FCM in 28 cases (23 ALL, 5 ANLL) and may be an important source of leukemia cell heterogeneity. The degree of DNA content abnormality detected by FCM was highly correlated (r = 0.98) with the number of whole chromosome gains or losses in the leukemia karyotype. Aneuploidy detectable by FCM was more frequent in acute lymphoblastic leukemia (ALL) (52 of 173, 30.1%) than in acute nonlymphoblastic leukemia (2 of 52, 3.8%) (p less than 0.001). In the ALL group, aneuploidy was significantly correlated with the cell surface expression of common ALL antigen: 46 of 127 antigen-positive cases were aneuploid compared to 6 of 46 antigen-negative cases (p less than 0.003). Only 2 of 21 cases of T-cell ALL without common ALL antigen had detectable aneuploidy, which was significantly less than in the common ALL group (p = 0.02). The median percentage of cells in S-phase was significantly greater for B-cell and erythrocyte rosette-positive T-cell ALL, than for the other phenotypic subgroups. We conclude that aneuploidy and S-phase cell percentage are correlated with the state of leukemia cell differentiation. The biologic basis for the correlation is not established, but may be linked to the process of malignant transformation.

Acute Disease↗
PubMed1981

Fatal Epstein-Barr virus infection in a child with acute lymphoblastic leukemia in remission.

A 9-year-old white boy developed a fatal primary Epstein-Barr virus (EBV) infection while receiving chemotherapy for acute lymphoblastic leukemia in remission. Histopathological findings at the height of the proliferative phase of the illness were compatible with a virally induced hemophagocytic syndrome. The infection spontaneously converted to complete aplasia of the bone marrow and lymph nodes. Serological studies disclosed that the patient had no antibodies to EBV prior to the infection, but during the acute phase he showed a spectrum and titers of antibodies to EBV-specific antigens characteristic of a current primary EBV infection. A lymph node biopsy obtained 5 weeks after onset revealed Epstein-Barr nuclear antigen in approximately 50% of the cells. The boy's condition deteriorated rapidly, with disseminated candidiasis resulting in cardiorespiratory failure and death. Lymph nodes obtained at autopsy no longer contained Epstein-Barr nuclear antigen-positive cells.

Animals↗
PubMed1981

Near-haploid acute lymphoblastic leukemia: a unique subgroup with a poor prognosis?

We describe two adolescent girls with acute lymphoblastic leukemia (ALL) whose leukemia cells were near-haploid. Their lymphoblasts stained in a block pattern with periodic acid Schiff and had "common ALL" surface markers confirmed by indirect immunofluorescence. Each patient had two populations of blasts, one near-haploid and one hyperdiploid, which was an exact doubling of the near-haploid karyotype. The first patient had a predominant population of cells with 26 chromosomes and a few with 52, while the second had a predominance of cells with 56 and a minority with 28. Flow cytometric analysis of DNA content initially detected the minor near-haploid population in the second patient, which was confirmed later by cytogenetic review of the marrow sample. In addition to our two patients, only four patients have been reported with near-haploid ALL. Of these six, five were girls, five were adolescents, and five had short survivals (median, 10 mo). All six had disomy of chromosome 21 with or without disomy for chromosomes 10, 14, 18, or X (four patients each). Thus, near-haploid ALL may represent a unique subgroup of ALL with a poor prognosis. To detect these and other possible subgroups, we have included cytogenetic analysis and flow cytometric analysis of DNA content in our initial evaluation of patients with ALL.

Acute Disease↗
PubMed1981

Computer simulation of the cellular immune response to malignant lymphoid cells: logic of approach, model design and laboratory verification.

A computer model was constructed to simulate the lymphocyte-mediated destruction of line Ib malignant lymphoid cells (Ib cells) as they circulated through the major tissue compartments of immune syngeneic C58 mice. The technique of discrete-event simulation was used to account for the arterial and venous circulation of blood-borne Ib cells through the lung, spleen, liver, and carcass. Simulation was carried out by means of IBM computer program 360, using the technique of General Purpose System Simulation. The parameters analysed were the mean residence times of viable and killed Ib cells in each tissue compartment, the rate or proliferation of Ib cells, the rate of generation of cytotoxic splenic lymphocytes, the rate of lysis of 51Cr labelled Ib cells, and the organ-specific rate constants for target cell kill. Direct laboratory measurements of these parameters validated the model and made it possible to calibrate computer simulations by the technique of best-fit analysis. The computer modelling technique accurately simulated the growth of viable Ib cells in vivo and the retention times of 51Cr in the spleen, lung, liver and carcass when viable or heat-killed Ib cells were inoculated intravenously (i.v.) into normal and immune mice. Computer simulations quantitatively defined the mean residence times of viable and heat-killed Ib cells in the major tissue compartments and the mean rate constants for target cell lysis in such compartments. The applicability of modelling approach to an analysis of immunological phenomena is discussed.

Animals↗
PubMed1980

Osteosarcoma, fibrous dysplasia, and a chromosomal abnormality in a 3-year-old child.

Osteosarcoma is a type of malignant bone tumor that is rare among children less than five years old. This report describes a 3-year-old boy with osteosarcoma of the right proximal femur and polyostotic fibrous dysplasia of the right femur and tibia. After hemipelvectomy, histologic examination of the amputated limb disclosed that the osteosarcoma had developed in a focus of fibrous dysplasia. Cytogenetic analysis of the patient's blood lymphocytes revealed a 4q-/7p + translocation in all cells. The patient's mother had an identical translocation but did not have a history of osteosarcoma or evidence of fibrous dysplasia. The chromosomal abnormality and the developmental osseous disorder may have predisposed this patient to developing osteosarcoma at an exceptionally young age.

Child, Preschool↗
PubMed1975

The effect of natural and surgically constructed aortopulmonary shunts on hemodynamic function in tetralogy of Fallot.

A hemodynamic model has been developed for the patient with tetralogy of Fallot. Equations representing the circulatory flow pattern and oxygen balance in this disease were incorporated into a computer program. With the computer model it is possible to simulate the effect of natural and surgically constructed aortopulmonary shunt flow on hemodynamic function in tetralogy of Fallot. Graphic representations of the computer output are presented which show how aortopulmonary shunt flow influences the physiology of exercise and hypoxic episodes. An explanation is advanced for the lack of correlation between resting arterial oxygen saturation and the incidence of hypoxic episodes. The model demonstrates the effect of surgical aortopulmonary shunts in eliminating hypoxic spells.

Aorta↗