Biomedical subjects

S Grant

Publications and source records attributed to S Grant.

At least 217 records · Page 12Linked to original sources

PubMed1992

Effect of a combined exposure to cytosine arabinoside, bryostatin 1, and recombinant granulocyte-macrophage colony-stimulating factor on the clonogenic growth in vitro of normal and leukemic human hematopoietic progenitor cells.

We have examined the effect of a combined 24 h exposure to cytosine arabinoside (ara-C) and the protein kinase C activator bryostatin 1, either alone or in conjunction with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), on the clonogenic growth of 14 primary samples from acute myelogenous leukemia (AML) patients, as well as normal human committed and early hematopoietic progenitors. Incubation of blasts with 1 microM ara-C and 12.5 nM bryostatin 1(+/- 1.25 ng/ml rGM-CSF) resulted in a heterogeneous pattern of inhibitory effects toward primary leukemic colonies, ranging from 32-98%, and subadditive to synergistic drug interactions. However, exposure of blasts to ara-C and bryostatin 1, either with or without rGM-CSF, eliminated leukemic cell self-renewal in 80-93% of samples, and very substantially reduced growth in the remainder. Exposure of normal human bone marrow mononuclear cells to identical concentrations of ara-C and byostatin 1 permitted the survival of 23% of committed myeloid progenitors (granulocyte-macrophage colony-forming units), and greater than 50% when rGM-CSF was included. Finally, exposure of bone marrow populations highly enriched for progenitor cells (CD34+, DR-, CD71-) to ara-C and bryostatin 1 +/- rGM-CSF for 24 h led to minimal reductions (e.g. 10-15%) in the survival of early hematopoietic progenitors (high proliferative potential colony-forming cells). Together, these findings indicate that combined exposure in vitro to ara-C and bryostatin 1, both with and without rGM-CSF, effectively inhibits the growth of leukemic cells with self-renewal capacity, while sparing a significant fraction of normal committed and primitive hematopoietic progenitors.

Adult↗

PubMed1991

c-kit expression by CD34+ bone marrow progenitors and inhibition of response to recombinant human interleukin-3 following exposure to c-kit antisense oligonucleotides.

The c-kit proto-oncogene encodes a receptor having tyrosine-specific kinase activity and has been mapped to chromosome 4 in the human and chromosome 5 in the mouse, at the dominant white spotting locus (W). Mutations at the W locus affect various aspects of murine hematopoiesis. The c-kit proto-oncogene has been shown to be expressed by leukemic myeloblasts, but not by normal unseparated human bone marrow cells. The role of this oncogene in differentiation and proliferation of human hematopoietic progenitors is presently undefined. To determine c-kit expression by normal hematopoietic progenitors, CD34+ cells were isolated from disease-free human bone marrow, and RNA-based polymerase chain reaction (PCR) techniques were used to assess expression. By this method, we have demonstrated c-kit expression by CD34+ bone marrow progenitors. To address the functional requirement for c-kit expression in normal human hematopoiesis, CD34+ cells were incubated in the presence of sense, antisense, or missense oligonucleotides to c-kit, and subsequently cultured in the presence of either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or recombinant human interleukin-3 (rhIL-3). Exposure of CD34+ cells to c-kit antisense oligonucleotides significantly inhibited colony-forming ability of cells cultured in the presence of rhIL-3, but had no effect on colony formation of cells cultured in rhGM-CSF. Together, these data suggest a possible role for c-kit in hematopoietic proliferation and differentiation that may be linked to some, but not all, stimulatory factors.

Antigens, CD↗

PubMed1991

Effects of thymidine and hydroxyurea on the metabolism and cytotoxicity of 1-B-D arabinofuranosylcytosine in highly resistant human leukemia cells.

We have examined the effect of the ribonucleotide reductase inhibitors thymidine (dThd) and hydroxyurea (HU) on the metabolism and cytotoxicity of high concentrations (10 to 100 mumol/L) of cytosine arabinoside (Ara-C) in a deoxycytidine kinase-deficient, highly Ara-C-resistant human promyelocytic leukemic cell subline (HL-60/Ara-C). Administration of dThd or HU (0.5 to 3 mmol/L) in conjunction with high concentrations of Ara-C either sequentially or simultaneously lead to enhanced (and in some cases a supra-additive) inhibition of HL-60/Ara-C suspension culture growth and soft agar colony formation. In addition, exposure of cells to 0.5 mmol/L dThd or HU for 48 hours significantly increased the percentage of HL-60/Ara-C in S-phase. In contrast to previous studies involving low-dose Ara-C administration, we were unable to detect dThd- or HU-mediated increments in Ara-CTP formation in HL-60/Ara-C cells treated with high-dose Ara-C despite reductions in intracellular dCTP pools as great as 65%. However, dThd or HU did increase Ara-C incorporation into newly synthesized DNA. These studies show that administration of dThd or HU in conjunction with high concentrations of Ara-C results in an enhanced antiproliferative effect of Ara-C against Ara-C-resistant leukemic cells deficient in deoxycytidine kinase.

Arabinofuranosylcytosine Triphosphate↗

PubMed1991

Treatment with interleukin-3 plus granulocyte-macrophage colony-stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts.

Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL-3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.

Acute Disease↗

PubMed1991

Exercise.

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Coronary Disease↗

PubMed1991

In vitro effects of bryostatin 1 on the metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine in human leukemia cells.

Bryostatin 1 is a macrocyclic lactone protein kinase C (PK-C) activator which has demonstrated promising antileukemic activity in preclinical studies. We have examined the effect of this agent on the metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) in both log phase and high-density human promyelocytic leukemia cells (HL-60). Exposure of low-density cells to 12.5 nM bryostatin 1 for 24 hr prior to a 4-hr incubation with 1 or 10 microM ara-C resulted in nearly a 2-fold increase in ara-CTP formation. When cells were maintained under high-cell density conditions (e.g. 5 x 10(6) cells/mL) for 24 hr prior to ara-C exposure, a 90% reduction in ara-CTP formation and ara-C DNA incorporation was observed. However, coincubation of high-density cells with bryostatin 1 for 24 hr increased ara-CTP formation 6- to 8-fold, yielding levels essentially equivalent to those achieved in low-density cells. Smaller (but still significant) increases in ara-C DNA incorporation were also noted. Enhancement of ara-CTP formation by bryostatin 1 occurred over a broad ara-C concentration range (0.1 to 100 microM), involved a temperature-dependent process, could not be mimicked by addition of hematopoietic growth factors, and was not related to neutralization of toxic or inhibitory substances in high-density medium. Exposure of cells to bryostatin 1 did not lead to morphologic or functional evidence of HL-60 cell maturation or an increase in cell viability, but did produce a decline in cellular proliferative activity as determined by thymidine and bromodeoxyuridine incorporation and cytofluorometric analysis. Bryostatin 1 did not exert its effects in high-density cells by inhibiting ara-C deamination or by interfering with ara-CTP dephosphorylation, but instead appeared to act by enhancing ara-C phosphorylation. Although cell-free extracts obtained from high-density cells exposed to bryostatin 1 exhibited levels of deoxycytidine kinase activity compared to controls, treated cells did display a significant decline in intracellular dCTP levels (e.g. 0.7 vs 1.3 pmol/10(6)), and nearly a 2-fold increase in ATP and UTP concentrations. Ara-CTP formation was also increased substantially by other PK-C activators including phorbol dibutyrate and mezerein (10-100 nM); this process was inhibited more than 70% by the PK-C inhibitor H-7 (50 microM), but not by the PK-C inhibitors staurosporine, tamoxifen, and HA1004. Finally, coadministration of ara-C and bryostatin 1 resulted in greater than expected inhibitory effects toward HL-60 cell clonogenic growth.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗

PubMed1991

The combination of a novel stimulatory element in the first exon of the maize Shrunken-1 gene with the following intron 1 enhances reporter gene expression up to 1000-fold.

Both exon 1 and intron 1 of the maize Shrunken-1 (Sh1) gene individually stimulate expression of reporter genes in transient gene expression experiments if present within the transcription unit. The Sh1 exon 1 mediates a 10-fold increase in activity when inserted at the 5' end of the bacterial chloramphenicol transacetylase (CAT) marker gene in both monocot and dicot protoplasts. The Sh1 intron 1 enhances chimeric gene expression in rice and maize protoplasts approximately 100-fold but inhibits CAT expression in tobacco protoplasts. In combination, the stimulatory effects of Sh1 exon 1 and intron 1 are multiplicative in monocot protoplasts resulting in a final enhancement of up to 1000-fold compared to the unmodified CAT or luciferase marker genes.

Base Sequence↗

PubMed1991

Submaximal, but not maximal, exercise testing detects differences in the effects of beta-blockers during treadmill exercise: a study of celiprolol and atenolol. II.

Celiprolol is a new-generation beta-blocker with ancillary properties that include partial beta 2-agonism and direct vasodilating activity. The effects of atenolol and celiprolol on maximal exercise capacity and on both respiratory variables and subjective indices of breathlessness and fatigue during submaximal exercise were compared in a placebo-controlled crossover study of 12 trained volunteers. Both atenolol and celiprolol equally and significantly reduced exercise capacity and maximal oxygen consumption. During constant submaximal exercise at 70% maximal oxygen uptake, however, differences emerged between the two beta-blockers. Atenolol was associated with a significantly higher minute ventilation than placebo. In contrast, values for minute ventilation and respiratory exchange ratio with celiprolol were similar to values with placebo. During the early stages of exercise, treatment with atenolol was also associated with higher scores for the subjective indices of breathlessness and fatigue. Thus submaximal exercise, which may be physiologically more relevant to the everyday activities of patients, may demonstrate potentially useful differences between drugs that are not seen during maximal exercise testing.

Adrenergic beta-Antagonists↗

PubMed1991

Angina, ischemia, and effort tolerance with vasodilating beta-blockers.

beta-Blockers are known to suppress exercise-induced ischemia but give rise to such problems as fatigue or dyspnea on effort and also bradycardia. In a series of double-blind, placebo-controlled studies of celiprolol (a cardioselective beta 1-blocker with beta 2-agonist and vasodilatory properties) in patients with hypertension and angina and in normal volunteers, it was found that celiprolol did not produce bradycardia when given in combination with verapamil. Celiprolol did reduce exercise-induced ischemia, but there was no reduction in cardiac output at rest or on exercise compared with placebo. Compared with atenolol, celiprolol produced less dyspnea and fatigue at submaximal levels of exercise. It is concluded that celiprolol possesses certain differences, compared with conventional beta-blockers, that may be of direct clinical benefit.

Adrenergic beta-Antagonists↗

PubMed1991

Effect of tetrahydrouridine and deoxytetrahydrouridine on the interaction between 2'-deoxycytidine and 1-beta-D-arabinofuranosylcytosine in human leukemia cells.

The interaction between 2'-deoxycytidine (dCyd) and 1-beta-D-arabinofuranosylcytosine (ara-C), administered at pharmacologically achievable concentrations, was examined in four continuously cultured human leukemia cell lines, HL-60, KG-1, K-562, and CCRF-CEM. In three of the cell lines (HL-60, K-562, and CCRF-CEM), co-administration of 20 or 50 microM dCyd with 10 microM ara-C reduced ara-CTP formation by at least 90% and incorporation of ara-C into DNA by at least 80%. In contrast, KG-1 cells exhibited substantially smaller reductions in both ara-CTP formation and incorporation of ara-C into DNA under identical conditions. KG-1 cells were distinguished by the highest activity of the enzyme cytidine deaminase of the four lines assayed, and exhibited the smallest increments in the intracellular accumulation of both dCyd and deoxycytidine triphosphate (dCTP) in response to exogenous dCyd. Co-administration of 1 mM tetrahydrouridine (THU) or 0.5 mM deoxy-tetrahydrouridine (dTHU) had little effect on the ability of dCyd to antagonize ara-C metabolism in HL-60, KG-1 and K-562 cells. In contrast, these deaminase inhibitors substantially increased the intracellular accumulation of dCTP as well as the ability of dCyd to antagonize ara-CTP formation and incorporation of ara-C into DNA in KG-1 cells. THU and dTHU also permitted dCyd to antagonize ara-C growth inhibitory effects in KG-1 cells to the extent observed in the other leukemic cell lines. These studies suggest that the intracellular deamination of exogenous deoxycytidine may influence the degree to which this nucleoside antagonizes ara-C metabolism and toxicity in some leukemic cells. They also raise the possibility that deaminase inhibitors may be employed to modulate, and perhaps to improve, the therapeutic selectivity of pharmacologically relevant concentrations of ara-C and dCyd in the treatment of acute leukemia in man.

Arabinofuranosylcytosine Triphosphate↗

PubMed1991

Transplantation of beta cells from transgenic mice into nude athymic diabetic rats restores glucose regulation.

We have shown that elevated plasma D-glucose levels in experimentally-induced diabetic nude athymic rats can be reduced by intraperitoneal transplantation of microcarrier-attached insulin producing beta cells from the mouse pancreatic beta cell line, beta TC-1. The reduction in the level of hyperglycemia was observed as early as two days following cell transplantation and was associated with a concomitant increase in plasma insulin levels. beta TC-1 cell transplanted diabetic rats had plasma D-glucose levels similar to those found in non-diabetic control animals and remained normoglycemic throughout the 39 day experimental period. The beta TC-1 cell transplanted diabetic rats also had near normalization of body weight, food and water intake and of urine output when compared to control diabetic and non-diabetic rats. Similarly, they exhibited improved blood glucose clearance following intravenous D-glucose administration. These results suggest that beta TC-1 cells regulate D-glucose homeostasis following transplantation into diabetic rat recipients in a manner similar to that of endogenous pancreatic beta cells.

Animals↗

PubMed1991

Mechanism of anomalous retinal correspondence: maintenance of binocularity with alteration of receptive-field position in the lateral suprasylvian (LS) visual area of strabismic cats.

We have examined the effects of rearing kittens with a unilateral convergent strabismus, induced surgically at 3 weeks of age, on the binocularity (ocular dominance) and receptive-field position of neurons in the motion-sensitive lateral suprasylvian (LS) area of cat extrastriate cortex. Data were compared to those obtained from area 17 in the same animals, and from the two areas of cortex in normal adult cats. Interocular alignment of the operated cats was assessed in alert adults using corneal reflex photography and during recording from the positions of retinal landmarks under paralysis. The strabismus magnitude in each operated cat was calculated by comparison with equivalent data from the normal animals. Strabismus always caused a major loss of binocularity in area 17. The remaining binocular neurons had receptive-field (RF) pairs arising from positions of normal correspondence in the two retinae and would thus have been responsive to different regions of visual space through the misaligned eyes in the alert animal. In area LS, the effects were dependent on the strabismus magnitude. In the group of four cats with pronounced strabismus (18-30 deg crossed), a loss of binocularity occurred in area LS equivalent in severity to that in area 17. The majority of the remaining binocular LS neurons possessed RF pairs in normal retinal correspondence and would thus, in the alert animal, have received spatially disparate visual input through the two eyes. This also occurred in three other cats with more moderate strabismus (11-15 deg crossed), although only a small breakdown in the binocularity of area LS was apparent. The group of cats with mild strabismus (less than or equal to 10 deg crossed) had normal proportions of binocular neurons in area LS. In three of these cats, the maintenance of binocularity was accompanied by shifts in RF position, with visual inputs arising from anomalous retinal locations. These shifts compensated, in part, for the strabismus angle present in each cat, so that most of the binocular LS neurons would have received inputs from regions of visual correspondence through the misaligned eyes when the animal was alert. Similar mechanisms could afford a basis for the binocular visual compensations that occur in humans with small-angle strabismus of early onset. If so, anomalous retinal correspondence in such individuals would have as a locus areas of extrastriate cortex with a role in motion perception, and would involve alterations to the neural substrate underlying normal binocular vision.

Animals↗

PubMed1991

Visuotopic organization of the lateral suprasylvian area and of an adjacent area of the ectosylvian gyrus of cat cortex: a physiological and connectional study.

We have explored the visuotopic organization of the territory surrounding the middle suprasylvian sulcus (MSS) of cat cerebral cortex by electrophysiological mapping, and by tracing the topography of its cortical and subcortical connections using wheatgerm-agglutinin horseradish peroxidase (WGA-HRP). Observations from the two approaches were concordant, and confirmed the presence of two separate visual areas in the MSS that approximate, but do not exactly correspond, to the location and internal organization of the posterior medial and posterior lateral lateral suprasylvian (PMLS, PLLS) areas of Palmer et al. (1978). We define as part of the lateral suprasylvian (LS) area the territory on the medial bank and caudal end of the lateral bank of the MSS that receives a topographically organized projection from the region of area 17 representing the lower visual quadrant. This territory is connected with other structures that are themselves striate-recipient (cortical areas 18 and 19, and the lateral division of the lateral posterior (LPl) nucleus), and with a variety of nuclei that receive direct retinal input, such as the C-laminae of the LGd, the medial interlaminar nucleus (MIN), and the superficial layers of the superior colliculus (SC). Its connections with the LPl, LGd, MIN, and SC correspond topographically with the input from area 17. Revised maps of area LS were produced from the physiological and connectional data: its rostral border is formed by a representation of lower visual elevations with the horizontal meridian represented caudally, and its lateral border is formed by the vertical meridian; area LS shares a representation of the center of gaze with the visual area of the lateral bank at its caudal end. The adjacent lateral bank area has larger receptive fields than area LS, and very different connectivity. It receives no input from area 17 and little input from striate-recipient structures, including area LS, but instead is connected to more remote extrastriate visual areas, such as the anterior ectosylvian visual (AEV) area in insular cortex, and to zones of the thalamus in receipt of tectal input (LPm and the lateromedial-suprageniculate nuclear complex). According to both mapping approaches, the lateral bank area contains representations of both the upper and lower visual quadrants but a rather limited degree of visuotopic order. We refer to it as the posterior ectosylvian visual (PEV) area, because it appears to be functionally and connectionally dissociated from area LS, but is possibly a functional antecedent of area AEV.

Animals↗

PubMed1991

Organization of reciprocal connections between area 17 and the lateral suprasylvian area of cat visual cortex.

The lateral suprasylvian (LS) area (or Clare-Bishop area) is a region of visual cortex in the cat which has been defined as an isolated projection zone of area 17 (V1 or striate cortex) within the suprasylvian sulcus. We have studied the overall topography and detailed pattern of connection between these two visual areas following injections of WGA-HRP into one or the other. The projection from area 17 to LS is formed largely (approximately 90%) from supragranular layer neurons that are distributed, in the coronal plane, in multiple regularly spaced patches. These patches are especially prominent in regions of area 17 representing central vision along and around the horizontal meridian. In reconstructions of serial coronal sections, and in flatmounts of the same region, the patches are seen to align so that in the plane tangential to the cortical surface they appear as a system of parallel bands whose main axis of elongation is rostro-ventral to caudo-dorsal, or near parallel to the area 17/18 border. The mean periodicity of the bands is about 1.0 mm. The projection from area 17 terminates mainly in layers 4, 3, and 2 of area LS, and also appears patchy in the coronal plane. Reconstruction of the cortical surface view again reveals a system of rostrocaudal bands, but with a mean periodicity of 2 mm. The back projection is less periodically organized, arising predominantly (approximately 80%) from a continuous sheet of infragranular neurons in area LS and terminating mainly in layer 1 of area 17, across the underlying patch and interpatch zones of the supragranular projection cells. However, neurons in layers 2 and upper 3 of area LS, which form the minority origin of the back projection, are mostly located in columnar registration with the patches of area 17 terminals. The bands of supragranular layer neurons projecting to area LS are aligned obliquely to the iso-orientation domains of area 17, indicating a further component to its organization. It is suggested that this may correspond to a segregation of the X and Y channels in area 17, with outputs to area LS selectively arising from the Y pathway, in accordance with previous reports.

Animals↗

PubMed1991

Effect of pharmacologic manipulation of protein kinase C by phorbol dibutyrate and bryostatin 1 on the clonogenic response of human granulocyte-macrophage progenitors to recombinant GM-CSF.

The effect of pharmacologic manipulation of protein kinase C (PK-C) activity on the response of committed human myeloid progenitor cells (CFU-GM) to recombinant human granulocyte-macrophage colony stimulating factor (rGM-CSF) was assessed. Coadministration of the PK-C activating agents, phorbol dibutyrate (PDBu) or bryostatin 1, with rGM-CSF resulted in a dose-dependent and, under some conditions, highly synergistic increase in the number of CFU-GM. With optimal combinations, colony formation far exceeded that which could be obtained with high concentrations of rGM-CSF alone. High concentrations of PDBu (e.g. greater than or equal to 50 nM), but not bryostatin 1, completely inhibited the CFU-GM response. These inhibitory effects could be reversed by bryostatin 1, but not by high concentrations of rGM-CSF. Bryostatin 1 also potentiated colony formation in response to rGM-CSF, and blocked the inhibitory effects of high concentrations of PDBu in bone marrow cells highly enriched for progenitors bearing the MY-10 antigen. The increase in CFU-GM induced by PDBu or bryostatin 1 was associated with little change in the morphologic type of colony observed. Continuous exposure of cells to the calcium ionophore, ionomycin (500 nM), reduced the number of granulocyte-macrophage colonies, but produced little change in the concentration-response of rGM-CSF and PK-C activating agents. Finally, the PK-C inhibitors H-7 and tamoxifen, when administered at concentrations exhibiting minimal inhibitory effects in the presence of rGM-CSF alone, led to no change or small increases in the numbers of colonies formed in response to rGM-CSF and bryostatin-1, and a substantial increase in the number of colonies formed in the presence of rGM-CSF and PDBu. These results suggest that PK-C activation may play a complex role in regulating the response of normal myeloid progenitors to growth factors such as rGM-CSF. They also raise the possibility that under some circumstances the phorbol ester PDBu may trigger events that inhibit the growth of myeloid progenitors, and that this process may be blocked by bryostatin 1.

Bryostatins↗

PubMed1991

A comparative study of left ventricular structure and function in elite athletes.

Adaptations to left ventricular (LV) structure and function appear to be dependent on the type, intensity and duration of exercise training. We therefore studied two clearly defined groups of elite athletes, by M-mode and Doppler echocardiography, with a group of inactive individuals as controls. All groups were age matched. Group 1 comprised ten elite endurance athletes with maximal oxygen consumption (VO2 max) of 74.7 +/- 1.43 (mean +/- SEM). Group 2 consisted of ten elite weightlifters with VO2 max 45.3 +/- 2.00. Group 3 comprised of ten inactive individuals with VO2 max 44.5 +/- 2.13. Left ventricular end diastolic dimension was significantly higher in group 1 (5.72 +/- 0.07) than in groups 2 or 3 (5.29 +/- 0.09 and 5.19 +/- 0.09 respectively, p less than 0.001). Left ventricular mass index was significantly higher in groups 1 and 2 (156.4 +/- 5.97 and 138.6 +/- 7.27 respectively) than in group 3 (104.1 +/- 3.16 p less than 0.001). Percentage fractional shortening was used as an index of systolic function and no significant difference was found between groups. Doppler E:A ratio was taken as an index of diastolic function and was found to be significantly elevated in group 1 at rest (3.37 +/- 0.24) compared with 2.38 +/- 0.16 and 1.99 +/- 0.10 in groups 2 and 3 respectively (p less than 0.003). On exercise, the E:A ratio in group 1 was significantly higher than in group 3 (1.95 +/- 0.14 and 1.23 +/- 0.05 respectively p less than 0.001), and tended to be higher than group 2 (1.68 +/- 0.15 p = ns). These data show that both modes of intense training produce left ventricular hypertrophy. Diastolic function is not impaired in the athletes and may be augmented in the endurance athletes.

Adolescent↗

PubMed1991

Differential effect of interleukin 3 on the metabolism of high-dose cytosine arabinoside in normal versus leukemic human bone marrow cells.

We have examined the effect of recombinant interleukin 3 (rIL-3) on the metabolism of high-dose cytosine arabinoside (Ara-C), an S-phase-specific agent, in normal human bone marrow mononuclear cells (BMMC) and leukemic blasts from patients with acute myeloid leukemia (AML). Exposure to rIL-3 for 24 h significantly increased the percentage of cycling S-phase cells in normal BMMC as well as leukemic cells. A concomitant expansion of intracellular deoxycytidine triphosphate (dCTP) levels occurred to a significantly greater extent in normal BMMC. Compared to treatment with Ara-C (10 mumol/liter) alone, prior and coadministration of rIL-3 with Ara-C increased Ara-CTP levels in leukemic blasts. However, an identical treatment produced significantly higher dCTP levels in normal BMMC, resulting in a significantly lower mean Ara-CTP to dCTP pool ratio in normal BMMC compared to that observed in each of the samples of AML blasts. Following treatment with Ara-C plus rIL-3 versus Ara-C alone, the alteration in Ara-C DNA incorporation corresponded with the change in Ara-CTP to dCTP ratio observed in normal BMMC and AML blasts. The differential effect of rIL-3 on the metabolism of high-dose Ara-C in normal versus leukemic cells may indicate a role for rIL-3 in enhancing the selectivity of Ara-C toward leukemic myeloblasts.

Bone Marrow↗

PubMed1991

Effect of pharmacologically relevant concentrations of mitoxantrone on the in vitro growth of leukemic blast progenitors.

The inhibitory effects of a 1 h exposure to pharmacologically relevant concentrations of the anthracenedione mitoxantrone were assessed with respect to the in vitro clonogenic growth of leukemic myeloblasts obtained from patients with acute myelogenous leukemia (AML). A steep mitoxantrone dose-response curve was observed, and increases in drug concentrations at both low and high dose ranges were associated with a significant potentiation of anti-leukemic effects. In particular, mitoxantrone concentrations of 1 microM or greater were highly inhibitory to leukemic blast progenitor cell growth, and were also effective in reducing or eliminating leukemic cell self-renewal capacity in those samples assayed. These findings suggest that mitoxantrone mediated lethal effects towards leukemic cells are dose-related within a pharmacologically achievable range, and raise the possibility that an increase in plasma levels through dose escalation might lead to enhanced leukemic cell killing in vivo.

Cell Division↗