Biomedical subjects

S Bruno

Publications and source records attributed to S Bruno.

At least 91 records · Page 5Linked to original sources

PubMed1993

Characterization of lineage-negative blast subpopulations derived from normal and chronic myelogenous leukemia bone marrows and determination of their responsiveness to human c-kit ligand.

Lineage-negative (lin-) normal and chronic myelogenous leukemia (CML) marrow blast populations were obtained by negative selection and subsequently separated on the basis of size by velocity sedimentation. The three subpopulations of lin- blasts obtained were enriched for F8 (the more primitive small blasts), F11 (blasts intermediate in size), and F13 (the more mature large blasts). We examined the morphological and phenotypic characteristics and cell cycle status of the subpopulations and determined the responsiveness of granulocyte-monocyte progenitors (colony-forming units/granulocyte-macrophage) derived from each subpopulation to mast cell growth factor in combination with granulocyte (G-CSF) or granulocyte-macrophage (GM-CSF) colony-stimulating factors alone and in combination. Morphological assessment revealed that an increased proportion of CML lin- blasts exhibited early cytoplasmic maturation as evidenced by the appearance of azurophilic (nonspecific) granules in the cytoplasm. Although the percentages of CML and normal small blasts expressing CD34 were similar, the proportion of CML lin- blasts expressing CD34 declined in the intermediate and more mature large lin- blast subpopulations by about 50%, whereas the percentage of CD34+ normal blasts remained essentially the same, indicating an earlier loss of CD34 expression by CML lin- blasts. In addition, the percentages of CML small blasts expressing CD33 were higher than normal (26-61% versus 0-16%, respectively), indicating that a higher proportion of CML small lin- blasts had a more mature phenotype. Mast cell growth factor addition to cultures stimulated by G-CSF, GM-CSF, or G-CSF plus GM-CSF, exerted the greatest synergistic effect (increased colony number and size) in the normal small and intermediate lin- blast cultures, but mast cell growth factor had considerably less effect, or no effect, in cultures of comparable CML subpopulations, indicating that CML lin- progenitors had a somewhat lower requirement for multiple growth factors. The findings suggest that the differences observed between normal and CML marrow subpopulations are proportional differences and that a greater proportion of CML lin- blast subpopulations exhibit characteristics associated with a more advanced stage of maturation than comparable normal lin- blast subpopulations.

Bone Marrow↗

PubMed1993

Myocyte DNA synthesis with aging: correlation with ventricular loading in rats.

To determine whether the detrimental mechanical and anatomical changes that occur biventricularly with aging are associated with activation of DNA synthesis, flow cytometric analysis was performed on myocyte nuclei prepared from the left and right ventricles of rats at 4, 12, 20, and 29 months of age. Heart weight increased significantly with age, and this growth adaptation was associated with the development of left ventricular failure and right ventricular dysfunction. These phenomena were coupled with marked elevations in diastolic wall stress and increases in the percentage of myocyte nuclei in S+G2M in both ventricles. Linear regression analyses revealed a direct correlation between the fraction of myocytes that entered the cell cycle and diastolic pressure and wall stress. An inverse relation was found between the percentage of myocyte nuclei in S+G2M and +dP/dt and systolic wall stress. Thus the depression of hemodynamic performance coupled with alterations in the loading conditions contributes, at least in part, to increased DNA synthesis in cardiac myocytes with age.

Aging↗

PubMed1993

Differences in the composition and in the efficiency of red cell production of normal and CML erythroid progenitor populations are highlighted by response to human c-kit ligand.

Previous studies have suggested that erythroid progenitors derived from patients with chronic myelogenous leukemia (CML) in chronic phase may have reduced proliferative capacity. Considering recent evidence that mast cell growth factor (MGF) enhances the proliferative capacity of normal erythroid burst-forming units (BFU-E), we examined whether MGF could increase the proliferative potential of CML erythroid progenitors to normal capacity. To evaluate the total proliferative capacity achieved, the BFU-E were divided into four subpopulations (XL = extra large, L = large, M = medium, S = small) and colonies were aspirated to determine the cellularity of BFU-E from each subpopulation. MGF alone or in combination with MoT cell line conditioned medium (MoCM) or granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin-3 (IL-3) significantly increased the proliferative capacity of erythropoietin (EPO) dependent CML and normal BFU-E. Although the total number of BFU-E generated were similar, the number of BFU-E with high proliferative potential were considerably less in CML BFU-E populations. BFU-E designated XL (129,000-431,000 cells) were only found in MGF cultures and only normal BFU-E had this proliferative capacity. BFU-E designated L were increased in both normal and CML BFU-E populations but less CML BFU-E had this proliferative capacity (mean number 25% of normal) and CML L BFU-E from 2/3 CML patients comprised fewer cells than normal L BFU-E. Normal BFU-E populations comprised 16-24% high proliferative BFU-E (XL + L) in contrast to 4-5% high proliferative BFU-E (L only) comprising CML BFU-E populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells, Cultured↗

PubMed1993

Epidoxorubicin and high dose leucovorin plus 5-fluorouracil in advanced gastric cancer: a phase II study.

We conducted a multicentric phase II study on advanced gastric cancer to determine the efficacy and toxicity of treatment with epidoxorubicin (EPI) plus high doses of leucovorin (LV) and 5-fluorouracil (5-FU). Thirty-seven patients with measurable disease were enrolled into the trial and treated with EPI 75 mg/m2 on day 1 and LV 200 mg/m2 plus 5-FU 450 mg/m2 from day 1 to 3, the cycle being repeated every 3-4 weeks from a median of five cycles per patients. The response rate was 49% in 35 evaluable patients, with two complete remissions and 15 partial responses. Median response duration was 12.4 months; median survival for responding patients was 17.3 months, which was significantly longer than 8.7 months for non-responding patients. General toxicity was usually mild, myelotoxicity was moderate and there was no evidence of cardiac toxicity. These results show that EPI-LV-5-FU is an effective regimen for advanced gastric carcinoma. The efficacy of this combination should now be tested as an adjuvant therapy in resectable gastric cancer.

Adult↗

PubMed1993

[Comparative study of 1st generation versus 2d generation (CAVPE) combinations in intermediate and high-grade lymphomas].

PURPOSE: To compare four first generation chemotherapy regimes (FGR) used by GATLA in low and intermediate grade lymphomas. Versus a second generation regimen called CAVPE. PATIENTS AND METHODS: A group of 205 patients treated with FGR (79 with BACOP, 89 with COPP, 19 with CHOP, and 18 with CNOP), and 244 others treated with the combination of cyclophosphamide, doxorubicin, vincristine, prednisone and etoposide (CAVPE) were included. Two randomized phase III multicentric studies, COPP vs BACOPP and CHOP vs CNOP, as a whole group, were compared with the second generation scheme, CAVPE. All the patients with FGR received 6 monthly treatment courses, and the CAVPE patients were given 8 monthly courses. RESULTS: The median age was 55 years (18-85) for the FGR group and 51 years (15-79) for the CAVPE group. The stage distribution for both FGR and CAVPE groups was, respectively, as follows: II: 38 and 55 cases; III 80 and 84 cases; IV: 87 and 105 cases. No significant differences were found between both groups when comparing other characteristics of the patients, namely, sex, symptoms, mediastinal, abdominal or extranodal involvement, liver, spleen or bone-marrow infiltration, and bulky tumoural mass. The percentage of complete remission (CR) was 52% (107/205) in the patients treated with FGR, and 67% (163/244) in the CAVPE group (p < 0.001). The estimated probability of sustained first CR at 72 months was 38% for the FGR group and 54% for the CAVPE group (p = 0.0167), whereas 17% and 36%, respectively, of the evaluable patients were alive and well, with no signs of disease progression (p = 0.000). The 72-month survival was estimated in 32% and 51%, respectively, for each group (p = 0.0004). CONCLUSIONS: 1. CAVPE seems to offer better responses and disease-free survival in this non-selected group of low and intermediate lymphoma patients. 2. The better results in terms of CR and lower incidence of relapses attained with CAVPE with regard to FGR are probably related with a number of facts, such as the use of more aggressive drugs, higher doses, a better drug combination rationale, the inclusion of new drugs, such as etoposide, or a selection of the patients.

Adolescent↗

PubMed1993

[Role of surgery for non-Hodgkin lymphoma of the gastrointestinal tract].

From January 1974 to December 1990, 619 patients were submitted to surgical treatment for gastrointestinal carcinoma: 10 cases (1.61%) of non-Hodgkin's lymphomas were observed (4 of the stomach, 3 of the small intestine, 1 of the colon, 2 of the rectum). There were 5 men and 5 women, mean age 57.1 years (range 34-80). In 6 patients the diagnosis was performed with radiological investigations, in 4 with ultrasonography too. Endoscopy biopsy was unfit for diagnosis in the gastric localizations, while it was positive in both rectal localizations. Seven patients were operated and no postoperative morbidity or mortality was observed. The role of surgery is discussed, diagnosis for staging and therapy alone or associated with chemotherapy and/or radiotherapy.

Adult↗

PubMed1992

Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells.

Genistein (GEN) is an isoflavone known to inhibit both tyrosine protein kinases and DNA topoisomerase II. The effects of GEN on cell proliferation and cell cycle kinetics of human myelogenous leukemia HL-60 and lymphocytic leukemia MOLT-4 cell cultures were studied, and the data were compared to results obtained with normal human lymphocytes stimulated to proliferate with phytohemagglutinin. GEN concentrations greater than 50 micrograms/ml (185 microM) were cytotoxic to HL-60 and MOLT-4 cells following exposure for 24 h; in HL-60 cell cultures, a population of cells with decreased DNA content and nuclear fragmentation characteristic of apoptosis was observed within 8 h. The 50% inhibition concentration after 24 h of exposure for HL-60 and MOLT-4 cells was 8.5 and 13.0 micrograms/ml, respectively. Normal proliferating lymphocytes survived a 24-h exposure of up to 200 micrograms/ml GEN. Short-term (4-8 h) exposures of MOLT-4 or HL-60 cells to 5-20 micrograms/ml GEN resulted in a suppression of cell progression through S or through both S and G2 phases, respectively, while equivalent treatment had no effect on proliferating lymphocytes. A stathmokinetic experiment using MOLT-4 cells revealed that as little as 5 micrograms/ml GEN suppressed cell exit from S to G2 phase by 40%, with a terminal point of action at or near the S-G2 border. Cell progression through the very early portion of G1 phase (G1A, characterized by postmitotic chromatin decondensation) was also suppressed by approximately 40%, whereas cell advancement through the remainder of the G1 phase was not markedly affected. Longer (24 h) exposure of proliferating lymphocytes to 20 micrograms/ml GEN led to an S-phase arrest, while similar treatment of leukemic cells caused cell arrest in G2 phase and an increase in the number of cells entering the cycle at higher DNA ploidy. The mitogen-induced transition of lymphocytes from G0 to G1 phase was extremely sensitive to inhibition by GEN; the 50% inhibition concentration was 1.6 micrograms/ml. The chemotherapeutic value of GEN may be due to the fact that, in terms of cytotoxicity, this agent is more active against proliferating leukemic cells than against normal proliferating lymphocytes. The sensitivity of the G0 to G1 transition in normal lymphocyte cultures and the suppressive effect of GEN on the G1A exit in MOLT-4 cells both suggest that protein kinases involved in chromatin decondensation may be a target of this drug. In light of the observation that lymphocyte stimulation is sensitive to the presence of GEN, the drug is expected to be a strong immunosuppressant.

Apoptosis↗

PubMed1992

Comparison of spontaneous ascites filtration and reinfusion with total paracentesis with intravenous albumin infusion in cirrhotic patients with tense ascites.

OBJECTIVE: To compare the effectiveness and safety of spontaneous ascites filtration and reinfusion and total paracentesis plus intravenous albumin infusion in cirrhotic patients with tense ascites. DESIGN: Randomised trial of the two treatments. SETTING: Teaching hospital and district general hospital in Milan. PATIENTS: 45 consecutive cirrhotic patients with recurrent tense ascites and urinary sodium excretion rate less than 20 mmol/day. 35 fulfilled admission criteria and completed the study. 17 received spontaneous ascites filtration and 18 paracentesis plus albumin infusion. MAIN OUTCOME MEASURES: Body weight; urinary volume; serum and urinary electrolyte, serum fibrinogen, and plasma aldosterone concentrations; and plasma renin activity before the procedure and 24 hours and eight days afterwards. RESULTS: Both procedures were effective in all patients. Weight decreased in both groups and showed no substantial increase after eight days. In patients receiving ascites filtration, values decreased significantly (p less than 0.01) after 24 hours for platelet count (mean relative change 0.92; 99% confidence interval 0.86 to 0.98) and serum fibrinogen concentration (0.92; 0.88 to 0.98) but returned to pretreatment values after eight days; no laboratory and clinical signs of disseminated intravascular coagulation were noted. Three patients in this group had fever, which receded spontaneously. One patient in each group had dilutional hyponatraemia. CONCLUSIONS: Spontaneous ascites filtration and reinfusion is an effective treatment for tense ascites. Reinfusion of the patient's concentrated proteins provides savings without compromising safety.

Adult↗

PubMed1992

Cell cycle-related expression of p120 nucleolar antigen in normal human lymphocytes and in cells of HL-60 and MOLT-4 leukemic lines: effects of methotrexate, camptothecin, and teniposide.

Expression of the proliferation-associated nucleolar antigen p120 was studied by flow cytometry in human quiescent and phytohemagglutinin-stimulated lymphocytes, as well as in human lymphocytic (MOLT-4) and promyelocytic (HL-60) cell lines. Bivariate analysis of p120 and DNA content made it possible to correlate p120 expression with cell position in the cycle. Proliferating lymphocytes and MOLT-4 and HL-60 cells had a similar pattern of p120 expression. Populations of G1 cells, in all three cell types, were very heterogenous with respect to p120, and a threshold in G1 was observed. The cells with a p120 level below the threshold value did not enter S phase. An increase in p120 was observed during progression through S phase, and the antigen was maximally expressed in G2 cells. The p120/DNA content ratio, however, was highest in late G1 cells (G1B) and was declining during S and G2. The data thus suggest that p120 may be degraded during mitosis and that the postmitotic cells inherit little, if any, of this protein; the antigen then accumulates predominantly during G1, and must reach a threshold level to enable the cells to enter S phase. Antigen p120 could not be detected in noncycling lymphocytes nor in HL-60 cells induced to myeloid differentiation by growth in the presence of dimethyl sulfoxide. Treatment of MOLT-4 cells with pharmacological concentrations of methotrexate, camptothecin, or teniposide induced cell arrest in S or G2; expression of p120 in the arrested cells was unchanged from that of untreated MOLT-4 controls at the same phase of the cycle. The level of p120 was minimal in MOLT-4 or HL-60 cells arrested in M phase by vinblastine, but vinblastine had no effect on p120 fluorescence of interphase cells. Camptothecin or teniposide induced apoptosis selectively in S phase of HL-60 cells; apoptotic cells from camptothecin-treated cultures, however, despite the marked nucleolysis, still expressed p120. The data on the drug-treated cells indicate that the p120 level in tumors of patients may be used as a marker of tumor/malignancy even in clinical samples obtained during treatment.

Antigens, Neoplasm↗

PubMed1992

Constitutive expression of p53 protein in enriched normal human marrow blast cell populations.

Previous studies by others using metabolic labeling, cell lysis, and immunoprecipitation have reported elevated levels of p53 protein in blast cells derived from patients with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML), whereas p53 protein was not detected in normal light-density bone marrow cells. In this report, using the same detection methods, we confirm the negligible expression of p53 protein in normal light density marrow cells. However, we find clearly significant levels of p53 protein expression in enriched normal human marrow blast populations. Furthermore, using a panel of p53 specific monoclonal antibodies, we find the p53 protein constitutively synthesized by normal marrow blasts has the immunologic phenotype identified by PAb240 that reportedly recognizes a common conformational-dependent epitope on mutant p53. We have also found that the p53 immunologic subclass identified by PAb240 exists in normal human circulating lymphocytes either resting, serum starved, or PHA activated. In summary, it is clear that (1) normal marrow blast populations provide the appropriate control for assessing the levels of p53 protein expression in leukemic blast cells; and (2) PAb240 cannot be used to distinguish p53 mutated at the DNA level from normal p53 in fresh human hematopoietic cells.

Antibodies, Monoclonal↗

PubMed1992

Interleukin-3 dependent c-myc protein expression during the cell cycle of murine mast cells.

Aim of the study was to evaluate the relationship between the mitogenic stimulus interleukin-3 to normal murine mast cells and the cell cycle dependent expression of the nuclear c-myc protein. In order to do that on a cell by cell basis, we measured the nuclear c-myc protein simultaneously by flow cytometry, via specific monoclonal antibodies, and the DNA content via the intercalating dye propidium iodide. When cells were deprived from interleukin-3 (IL-3), proliferation was inhibited and the majority of cells arrested in early G1 (G1A, characterized by low c-myc content). Readdition of IL-3 resulted in a slow transition of cells from G1A to late G1 (G1B, at higher c-myc content) before DNA synthesis started. G1A cells with low c-myc content do not undertake DNA synthesis. Using a stathmokinetic methodology we confirmed that the G1A cells are early postmitotic G1 phase cells. The low content of c-myc within these cells appears a direct consequence of reduced c-myc levels during mitosis. Cumulatively, the data suggest that c-myc protein levels of murine mast cells fall at mitosis and that these levels must rise before cells can traverse the G1 phase. Our data are compatible with a model in which c-myc protein content of G1 phase cells has to reach a critical threshold before the cells can move further into the cell cycle.

Animals↗

PubMed1992

Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes.

Staurosporine, a microbial alkaloid, is a strong inhibitor of protein kinases. The effects of staurosporine on the cell cycle progression and nuclear morphology of normal human lymphocytes stimulated to proliferate by phytohemagglutinin were studied and compared with the effects of this drug on human lymphocytic leukemic MOLT-4 cells. Exposure of normal lymphocytes to either 5-10 or 50-100 ng/ml of staurosporine resulted in the preferential accumulation of cells in G1 or G1 and G2 phases of the cell cycle, respectively. In contrast, regardless of the concentration (5-100 ng/ml), staurosporine arrested MOLT-4 cells initially in G2; these cells then initiated additional rounds of DNA replication, without division. Staurosporine (5-100 ng/ml) induced severe changes in the nuclear morphology of MOLT-4 cells, manifested as nuclear elongation, deep invaginations of the nuclear membrane, extensive fragmentation, and micronucleation. At concentrations of 5-10 ng/ml, staurosporine had no apparent effect on the nuclear morphology of normal lymphocytes and at 50-100 ng/ml it produced minor changes in the nuclear shapes of these cells. The data indicate that the kinase(s) involved in the regulation of cell exit from G1 and G2, respectively, in normal and leukemic lymphocytes may have different sensitivities to staurosporine, which suggests that the mechanisms controlling exit from G1 in these cells may be different. In MOLT-4 cells the staurosporine-sensitive kinase(s) appear to also be involved in phosphorylation of nuclear constituents essential for organization of gross chromatin structure. The different response of normal versus leukemic lymphocytes to staurosporine, if confirmed on clinical material, opens new strategies of tumor treatment.

Alkaloids↗

PubMed1992

Effect of ionic strength in immunocytochemical detection of the proliferation associated nuclear antigens p120, PCNA, and the protein reacting with Ki-67 antibody.

This study was aimed at revealing whether or not ionic interactions between the epitope of the antigen detected by Ki-67 antibody, or the proliferation-associated proteins PCNA or p120, and neighboring cellular constituents impede detectability of these antigens in HL-60 cells by indirect immunofluorescence assay. To this end, the ionic strength (NaCl concentration) of the solutions in which cells were suspended during their fixation with 0.5% paraformaldehyde was increased, to up to 1.65 M NaCl, to weaken the intra- and/or intermolecular ionic interactions during the process of crosslinking, and the cells were then immunostained. Fluorescence of cells reacting with Ki-67 antibody was maximally increased after their treatment with 1.15 M NaCl; the average increase was nearly 110% above the level seen with the standard methodology utilizing 0.15 M NaCl. The increase was greater for cells in the G1 phase of the cell cycle compared to cells in S or G2. Fluorescence of cells stained with the PCNA antibody was maximally enhanced after cell treatment with 0.65 M NaCl. The enhancement, however, varied depending on the source of the antibody; it was nearly 200% in the case of the antibody provided by Boehringer and over 100% by DAKO. Detection of the nucleolar antigen p120 was not significantly affected by 0.65-1.65 M NaCl. The data indicate that ionic interactions between cellular constituents indeed play a role in masking the epitope of PCNA and the antigen detected by Ki-67.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Cycle↗

PubMed1992

Features of apoptotic cells measured by flow cytometry.

The present review describes several methods to characterize and differentiate between two different mechanisms of cell death, apoptosis and necrosis. Most of these methods were applied to studies of apoptosis triggered in the human leukemic HL-60 cell line by DNA topoisomerase I or II inhibitors, and in rat thymocytes by either topoisomerase inhibitors or prednisolone. In most cases, apoptosis was selective to cells in a particular phase of the cell cycle: only S-phase HL-60 cells and G0 thymocytes were mainly affected. Necrosis was induced by excessively high concentrations of these drugs. The following cell features were found useful to characterize the mode of cell death: a) Activation of an endonuclease in apoptocic cells resulted in extraction of the low molecular weight DNA following cell permeabilization, which, in turn, led to their decreased stainability with DNA-specific fluorochromes. Measurements of DNA content made it possible to identify apoptotic cells and to recognize the cell cycle phase specificity of the apoptotic process. b) Plasma membrane integrity, which is lost in necrotic but not apoptotic cells, was probed by the exclusion of propidium iodide (PI). The combination of PI followed by Hoechst 33342 proved to be an excellent probe to distinguish live, necrotic, early- and late-apoptotic cells. c) Mitochondrial transmembrane potential, assayed by retention of rhodamine 123 was preserved in apoptotic but not necrotic cells. d) The ATP-dependent lysosomal proton pump, tested by the supravital uptake of acridine orange (AO) was also preserved in apoptotic but not necrotic cells. e) Bivariate analysis of cells stained for DNA and protein revealed markedly diminished protein content in apoptotic cells, most likely due to activation of endogenous proteases. Necrotic cells, having leaky membranes, had minimal protein content. f) Staining of RNA allowed for the discrimination of G0 from G1 cells and thus made it possible to reveal that apoptosis was selective to G0 thymocytes. g) The decrease in forward light scatter, paralleled either by no change (HL-60 cells) or an increase (thymocytes) of right angle scatter, were early changes during apoptosis. h) The sensitivity of DNA in situ to denaturation, was increased in apoptotic and necrotic cells. This feature, probed by staining with AO at low pH, provided a sensitive and early assay to discriminate between live, apoptotic and necrotic cells, and to evaluate the cell cycle phase specificity of these processes. i) The in situ nick translation assay employing labeled triphosphonucleotides can be used to reveal DNA strand breaks, to detect the very early stages of apoptosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Activity of 4-HPR in superficial bladder cancer using DNA flow cytometry as an intermediate endpoint.

The ability of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) to affect the outcome of previously resected superficial bladder cancer was investigated in a pilot study using DNA content flow cytometry and conventional cytology as intermediate endpoints. Twelve patients were treated with oral 4-HPR (200 mg daily) and compared with 17 non-randomized, untreated controls. The median interval between transurethral resection and 4-HPR administration was 5.5 months (range 0-36). The median follow-up period was 12 months (range 3-31) in the 4-HPR group and 9 months (range 2-22) in the control group. The proportion of patients with DNA aneuploid stemlines in bladder-washed cells decreased from 7/12 (58%) to 5/11 (45%) in the 4-HPR group, but increased from 7/17 (41%) to 10/17 (59%) in the control group. In patients with stable diploid profiles, mean (+/- SE) S-phase and G2+M-phase fractions decreased in the course of retinoid treatment from basal levels of 15.2 +/- 4.1% to 7.5 +/- 3.3% and 10.3 +/- 2.2% to 5.2 +/- 0.4%, respectively. The same parameters in the control group changed from basal levels of 14.6 +/- 3.4% to 12.4 +/- 2.7% and 9.8 +/- 1.6% to 12.6 +/- 1.6%, respectively. Positive or suspicious cytologic examinations were present in 3/12 (25%) treated cases prior to 4-HPR administration and all subsequently reverted to normal. The same parameter in the control group increased from 4/17 (24%) to 6/17 (35%) during follow-up. Impaired adaptation to darkness was recorded in 4 patients, and transient dermatologic alterations were observed in one-third of the patients, requiring dose reduction in one case.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Effect of camptothecin on mitogenic stimulation of human lymphocytes: involvement of DNA topoisomerase I in cell transition from G0 to G1 phase of the cell cycle and in DNA replication.

The possible involvement of DNA topoisomerase I in cell transition from G0 to G1 and in progression through the cell cycle was studied by estimating the ability of human peripheral blood lymphocytes to undergo mitogenic stimulation in the presence of the topoisomerase I inhibitor camptothecin (CAM). Exposure of quiescent G0 lymphocytes to up to 3 microM CAM for 24 h had no significant effect on their ability to subsequently undergo mitogenic stimulation in the presence of phytohemagglutinin (PHA); higher doses of CAM, although not immediately cytotoxic, impaired the mitogenic response. Stimulation of lymphocytes with PHA in the presence of < or = 1.5 microM CAM resulted in unperturbed transition of these cells from G0 to G1 characterized as an increase in cellular rRNA content, appearance of interleukin-2 receptor, and, after removal of CAM, response to interleukin-2 by entering S phase of the cell cycle. However, lymphocytes were prevented from entering S phase in the presence of CAM at a concentration of > or = 30 nM, and their rate of progression through S was minimal even at CAM concentration as low as 3 nM. When cycling lymphocytes (48 h after stimulation by PHA) were treated with CAM, the cell progression through S and G2 was also very sensitive to the inhibitor: the cells were "frozen" in S and G2 at > or = 6 nM CAM. These cells died within 24 h; their selective loss from the cultures (with only G0/G1 cells remaining) coincided with the appearance of cells with fractional DNA content, typical of apoptotic cells. Human lymphocytic leukemic MOLT-4 cells were arrested in S and G2 at > or = 7.5 nM CAM. Thus, progressions through S and G2 of both normal and leukemic lymphocytes were perturbed at approximately two orders of magnitude lower CAM concentration than the G0 to G1 transition. These data suggest that DNA replication and chromosomal events during G2 are more sensitive to inhibition of DNA topoisomerase I, compared with the early events of lymphocyte stimulation, which involve activation and transcription of numerous genes associated with the G0 to G1 transition. The antitumor properties of CAM may be related to its high cytostatic/cytotoxic activity toward cycling cells and relative resistance of cells in G0 or undergoing transition from G0 to G1.

Camptothecin↗

PubMed1992

HCV infection in HBsAg positive chronic liver disease.

The prevalence of anti-HCV antibodies was determined for a group of 68 patients with various forms of chronic liver disease. All patients that were anti-HCV positive but did not show signs of HBV replication had severe liver disease. We therefore suggest that HCV may be responsible for liver damage in HBsAg positive subjects when there are no evident signs of HBV replication.

Chronic Disease↗

PubMed1992

HCV and HIV infection among intravenous drug abusers in eastern Sicily.

In a study of 175 intravenous drug addicts from Eastern Sicily, 58.3% were found to be anti-HCV positive. In this population, the presence of anti-HCV was independent of HIV infection, age, duration of drug use and the practice of needle sharing. This may indicate that HCV is more readily transmitted (or spread earlier in this population) among drug addicts than is HIV.

Female↗