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R N Taub

Publications and source records attributed to R N Taub.

At least 19 recordsLinked to original sources
PubMed2006

Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin-proteasome pathway as a therapeutic target in poor prognosis tumors.

Malignant mesothelioma is an aggressive neoplastic proliferation derived from cells lining serosal membranes. The biological and clinical characteristics of epithelial type malignant mesothelioma are distinct from those of biphasic and sarcomatous type tumors. The goal of our study was to examine the molecular basis for this distinction. Microarray analysis confirmed that the molecular signatures of epithelial and biphasic histologic subtypes were distinct. Among the differentially expressed functional gene categories was the ubiquitin-proteasome pathway, which was upregulated in biphasic tumors. Cytotoxicity experiments indicated that 211H cells derived from biphasic tumors were synergistically sensitive to sequential combination regimens containing the proteasome inhibitor bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of epithelial tumor origin, was apoptosis. Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.

Adult↗
PubMed2000

Peritoneal mesothelioma.

Malignant peritoneal mesothelioma is an aggressive neoplasm that rapidly spreads within the confines of the abdominal cavity to involve most accessible peritoneal and omental surfaces. Current treatments are unsatisfactory, and new approaches are needed. We have noted prolonged survival in selected patients after intensive multimodality treatment. Our current experimental regimen includes initial laparotomy with omentectomy, resection of peritoneal implants, and placement of bilateral peritoneal Port-a-Caths (Sims Deltec, Inc., St. Paul, MN); repeated courses of intraperitoneal chemotherapy with doxorubicin, cisplatin, and interferon gamma; second-look laparotomy and intraoperative hyperthermic perfusion with mitomycin and cisplatin; and whole abdominal radiation. Patients with peritoneal mesothelioma who are not candidates for this approach can sometimes be palliated with systemic (intravenous) chemotherapy using doxorubicin or mitomycin, alone or in combination with cisplatin or carboplatin. Newer agents such as gemcitabine and multitargeted antifolate (pemetrexed disodium, LY231514) show promise of greater effectiveness.

Antineoplastic Agents↗
PubMed1997

Chemotherapy for advanced sarcoma: therapeutic decisions and modalities.

In patients who have advanced soft tissue sarcoma that is no longer localized, systemic chemotherapy is the most reasonable option for treatment. The decision to treat or to use experimental or conventional agents should be based on the clinical assessment of anticipated net benefit in quality of life as well as the remote possibility of complete remission or even cure. Asymptomatic elderly patients with relatively stable disease might best be treated with watchful waiting; whereas younger excellent-performance-status patients should be offered the opportunity of participating in phase II or phase I studies of newer drugs and intensification regimens. Of the currently available single agents, only doxorubicin (or epirubicin) and ifosfamide show response rates greater than 20%; both show a definite dose-response relationship. Dacarbazine shows particular activity in uterine leiomyosarcomas. Combination chemotherapy regimens such as doxorubicin-ifosfamide show a higher response rate, but may be more toxic. New agents are needed. The current progress in our understanding of the molecular biology of sarcomas, and our expanded comprehension of the mechanism of action of cytotoxic drugs and the biology of drug resistance is cause for optimism.

Antineoplastic Agents↗
PubMed1997

Chemotherapy for malignant mesothelioma.

The treatment of malignant mesothelioma (MM) has been challenging. Many series from larger single institutions comprise small numbers of selected patients. Positive studies tend to be published, whereas publication of negative studies is delayed, appears in obscure journals, or does not occur at all. Because of the pleural distribution of the tumor, reliable determination of response is problematic. Finally, the natural history of MM is generally short, but can be quite variable. Nevertheless, doxorubicin, cisplatin, and ifosfamide and perhaps other agents as well have modest activity. Larger phase II studies are now being done by cooperative groups accruing patients from community hospitals as well as from tertiary care centers. In the Cancer and Leukemia Group B study, the response rate in patients with measurable disease was 24% for cisplatin and either mitomycin C and doxorubicin, the highest response rates reported for a cooperative group study. Survival was slightly better for the doxorubicin combination. Studies of new drugs and biologics as well as of novel methods of drug delivery are underway.

Antineoplastic Agents↗
PubMed1992

Homogeneously staining region in anthracycline-resistant HL-60/AR cells not associated with MDR1 amplification.

Anthracycline-resistant HL-60/AR cells and their drug-sensitive HL-60/S counterparts were characterized by karyotypic analysis and examined for the overexpression of DNA and mRNA sequences coding for P-glycoprotein (Pgp). The HL-60/S cells were karyotypically stable over a 5-year period of study (1986-1991), except for an additional small Giemsa-positive band noted at 7q22 in cultures harvested in 1987, but not in 1986. This change did not affect drug sensitivity. The drug-resistant HL-60/AR cells examined in 1986, 1987, and 1991 demonstrated a very stable karyotype. The most striking feature was a large homogeneously staining region in the long arm of chromosome 7 (7q11.2), and translocation of the remainder of the long arm to another centromere. Other changes in the HL-60/AR cells included inversion in 9q, partial deletion of the short arm of chromosome 10p, addition of material to the p arm of der(16), loss of chromosome 22, and the appearance of a new marker chromosome. Both HL-60/S and the HL-60/AR cells were found not to amplify DNA or mRNA sequences coding for the Pgp. Thus, although the HL-60/AR cells possess the classical multidrug resistance phenotype and demonstrate a homogeneously staining region near the region of the MDR1 gene, their resistance is due to mechanisms other than those coded for by MDR1.

Antibiotics, Antineoplastic↗
PubMed1991

Subcellular distribution of daunorubicin in P-glycoprotein-positive and -negative drug-resistant cell lines using laser-assisted confocal microscopy.

Four well defined multidrug-resistant cell lines and their drug-sensitive counterparts were examined for intracellular distribution of daunorubicin (DNR) by laser-assisted confocal fluorescence microscopy: P-glycoprotein-negative HL-60/AR cells, and P-glycoprotein-positive P388/ADR, KBV-1, and MCF-7/ADR cells. Both drug sensitive cell lines (HL-60/S, P388/S, KB3-1, and MCF-7/S) and drug-resistant cell lines (HL-60/AR, P388/ADR, KBV-1, and MCF-7/ADR) exposed to DNR showed a similar rapid distribution of drug from the plasma membrane to the perinuclear region within the first 2 min. From 2-10 min, the drug sensitive HL-60/S, P388/S, and MCF-7/S cells redistributed drug to the nucleus and to the cytoplasm in a diffuse pattern. In contrast, drug-resistant HL-60/AR, P388/ADR, and MCF-7/ADR redistributed DNR from the perinuclear region into vesicles distinct from nuclear structures, thereby assuming a "punctate" pattern. This latter redistribution could be inhibited by glucose deprivation (indicating energy dependence), or by lowering the temperature of the medium below 18 degrees C. The differences in distribution between sensitive and resistant cells did not appear to be a function of intracellular DNR content, nor the result of drug cytotoxicity. Drug-sensitive KB3-1 and -resistant KBV-1 cells did not fully follow this pattern in that they demonstrated an intracellular DNR distribution intermediate between HL-60/S and HL-60/AR cells with both "punctate" and nuclear/cytoplasmic uptake sometimes in the same cell. These data indicate that the intracellular distribution of DNR is an important determinant of drug resistance regardless of the overexpression of P-glycoprotein. The intracellular movement of drug requires the presence of glucose and a temperature above 18 degrees C, implicating energy-dependent processes and vesicle fusion in the distribution process. This intracellular transport of DNR away from the nucleus in multidrug-resistant cells may protect putative cell targets such as DNA against drug toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Membrane glycoprotein changes associated with anthracycline resistance in HL-60 cells.

The glycoproteins on the surface of HL-60/S wild-type, drug-sensitive human leukemia cells and HL-60/AR anthracycline-resistant cells which do not overexpress the P-glycoprotein, were characterized by labeling with [35S]-methionine, NaB[3H4], phosphorus 32, or sodium iodide I 125. HL-60/S and HL-60/AR cell lysates and membrane fractions tagged with [35S]-methionine or phosphorus 32 showed no significant differences in their protein patterns as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and by autoradiography. HL-60/S cells labeled with NaB[3H4] yielded glycoproteins that were smeared predominantly in the molecular-weight range of 210,000 and 160,000 Da, with pI values ranging between pH 4 and pH 4.4. In contrast, NaB[3H4]-labeled HL-60/AR cells showed 7-8 discrete glycoproteins within a molecular-weight range of 170,000 and 140,000 Da, with pI values also ranging between pH 4 and pH 4.4. In addition, [3H]-glucosamine incorporation into HL-60/S and HL-60/AR cells revealed that the latter showed lower uptake of [3H]-glucosamine than did the former. Following treatment with tunicamycin, [3H]-glucosamine uptake in HL-60/S cells decreased, whereas that in HL-60/AR cells remained unchanged. Surface-membrane radioiodination of HL-60/S and HL-60/AR cells showed two distinct protein electrophoretic patterns, with differences being observed in both the high-(220-95 kDa) and low-molecular-weight ranges (21 kDa). Flow cytometric analysis of HL-60/S and HL-60/AR cells using myeloid and lymphoid antigen-specific antibodies demonstrated no antigenic differences between HL-60/S and HL-60/AR cells. HL-60/S cells incubated in the presence of tunicamycin, an inhibitor of N-linked glycosylation, or the protein kinase C agonist phorbol 12-myristate 13-acetate (PMA) developed a glycoprotein pattern similar to that observed in HL-60/AR cells. In addition, tunicamycin treatment of HL-60/S cells decreased daunorubicin (DNR) retention and altered its intracellular distribution as compared with that in HL-60/AR cells. These data indicate that HL-60/AR cells do not possess either de novo or amplified high-molecular-weight surface-membrane proteins; instead, existing proteins are hypoglycosylated. These results also show that HL-60/AR cells exhibit the multidrug-resistant phenotype in association with altered membrane glycoproteins of both high (220-95 kDa) and low molecular weight (21 kDa), but without overexpression of the P-glycoprotein. Furthermore, in HL-60/S cells, the multidrug-resistant phenotype is partially inducible by inhibition of N-linked glycosylation of cell-surface proteins.

Antibiotics, Antineoplastic↗
PubMed1990

Human leukemic myeloblasts and myeloblastoid cells contain the enzyme cytidine 5'-monophosphate-N-acetylneuraminic acid:Gal beta 1-3GalNAc alpha (2-3)-sialyltransferase.

We have examined the role of CMP-NeuAc:Gal beta 1-3GalNAc-R alpha(2-3)-sialyltransferase in fresh leukemia cells and leukemia-derived cell lines. Enzyme activity in normal granulocytes using Gal beta 1-3GalNAc alpha-o-nitrophenyl as substrate was 1.5 +/- 0.7 nmol/mg/h whereas activity in morphologically mature granulocytes from 6 patients with chronic myelogenous leukemia (CML) was 4.2 +/- 1.6 nmol/mg/h (P less than 0.05). Myeloblasts from 5 patients with CML in blast crisis showed enzyme activity levels of 6.5 +/- 2.5 nmol/mg/h. From 2 patients with CML, both blasts and granulocytes were obtained, with higher enzyme activity in the patients' blasts (7.1 nmol/mg/h) than in their granulocytes (4.9 nmol/mg/h) in both cases, suggesting that the increase in enzyme activity is related to the differentiation or proliferation status of the CML cells. However, similarly high enzyme levels were also seen in myeloblasts from acute myeloblastic leukemia patients (5.6 +/- 1.4 nmol/mg/h) and in some acute myeloblastic leukemia-derived cell lines (KG1a and HL60), suggesting that increased levels of this enzyme are not directly correlated with the presence of the Ph1 chromosome. This alpha(2-3)-sialyltransferase activity can also be detected in normal peripheral blood lymphocytes and exhibits increased activity in chronic lymphocytic leukemia cells and acute lymphoblastic leukemia. These data suggest that the level of enzyme activity may vary with growth rate and maturation status in myeloid and lymphoid hemopoietic cells. Finally, we have identified a glycoprotein in acute myeloblastic leukemia cells that serves as a substrate for the alpha(2-3)-sialyltransferase. The desialylated form of the glycoprotein was resialylated in vitro by the purified placental form of this alpha(2-3)-sialyltransferase and exhibits a molecular weight of about 150,000.

Blast Crisis↗
PubMed1990

Architectural organization in the interphase nucleus of the protozoan Trypanosoma brucei: location of telomeres and mini-chromosomes.

We studied the spatial organization of chromatin in the interphase G1, S and G2 nucleus of the protozoan Trypanosoma brucei, applying in situ hybridization with conventional fluorescence and confocal scanning optical microscopy. The majority of the trypanosome telomere GGGTTA repeats from different chromosomes were found clustered together, either extending in a network through the nuclear interior or localized at the nuclear periphery. The population of one hundred mini-chromosomes was often asymmetrically located: either clustered in a narrow band in close association with the nuclear envelope or distributed into several clusters that segregated into roughly one half of the nucleus. The nuclear organization may undergo modifications during the cell cycle and development. We conclude that non-random spatial positioning of DNA exists in the nucleus of this protozoan. Finding a high level of structural organization in the interphase nucleus of T.brucei is an important first step towards understanding chromosome structure and functioning and its role in the control of gene expression.

Animals↗
PubMed1989

Intracellular distribution and pharmacokinetics of daunorubicin in anthracycline-sensitive and -resistant HL-60 cells.

Anthracycline-sensitive (HL-60) and -resistant (HL-60/AR) cells, which do not overexpress the P-glycoprotein, each transport and distribute daunorubicin (DNR) into distinct intracellular locations, as visualized by digitized video fluorescence microscopy. At pH 7.4, the fluorescence of DNR in HL-60 cells appears distributed diffusely in both the nucleus and cytoplasm. In contrast, HL-60/AR cells show much less fluorescence in the nucleus and cytoplasm; most of the fluorescence localizes first to the Golgi apparatus and is then gradually shifted to the lysosomes and/or mitochondria. In pharmacokinetic studies, HL-60/AR cells exposed to different extracellular concentrations of [14C]DNR consistently accumulated less radioactive drug than the parent HL-60 cells. Incubation of HL-60/AR cells with sodium azide and deoxyglucose blocked the efflux of [14C]DNR and also prevented the shift of DNR fluorescence from the Golgi apparatus to the lysosomes/mitochondria. The efflux and the intracellular shift of DNR could also be inhibited by lowering the temperature to 18 degrees C, which stops endosomal membrane fusion. When DNR was allowed to accumulate in HL-60 or HL-60/AR cells at pH 5 there was an increase in the proportion of drug fluorescence in the membranes of both HL-60 and HL-60/AR cells; a decrease in the amount of drug retained by HL-60, but not by HL-60/AR cells; and a decrease in the cytostatic effects of DNR on both HL-60 and HL-60/AR cells. These data suggest that DNR resistance is associated with a failure of DNR to pass through membranes and to bind to cytoplasmic and nuclear structures. Instead, most of the drug is taken up by the Golgi apparatus from which it is then shifted to the lysosomes or to mitochondria, or out of the cell.

Antibiotics, Antineoplastic↗
PubMed1989

Role of glutathione and dependent enzymes in anthracycline-resistant HL60/AR cells.

We studied the cellular enzymatic defenses against anthracycline-induced free radical damage in the HL60 human myelogenous leukemia cell line and in its anthracycline-resistant subline, HL60/AR. Intracellular glutathione (GSH) levels and gamma-glutamyl transpeptidase activity were lower in HL60/AR than in HL60 cells. Glutathione-S-transferase (GST) and glutathione peroxidase activities were similar in both cell lines. The intracellular distribution of GSH/GST was visualized by digitized video fluorescence microscopy, utilizing the fluorescent probe monochlorobimane fluorescence microscopy, utilizing the fluorescent probe monochlorobimane (MBCl), which is specifically conjugated to GSH by GST. In HL60 cells stained with the MBCl probe, a bright diffuse cytoplasmic and nuclear fluorescence pattern was observed, whereas in HL60/AR cells, the fluorescence was mostly localized to the Golgi apparatus with a lesser component of diffuse cytoplasmic and nuclear fluorescence. Pretreatment of HL60/AR cells with buthionine sulfoximine (BSO) partially reversed resistance to daunorubicin. This effect of BSO on resistance was associated not only with the abolition of localized MBCl fluorescence to the Golgi apparatus but also with increased intracellular accumulation and retention of daunorubicin. The results of our studies demonstrate that inhibition of GSH synthesis in HL60/AR cells results in significant sensitization to daunorubicin and suggest that changes in the intracellular distribution of GSH/GST and/or increased drug retention may be involved in mediating this effect.

Antibiotics, Antineoplastic↗
PubMed1987

Presence of cytidine 5'-monophospho-N-acetylneuraminic acid:Gal beta 1-3GalNAc-R alpha(2-3)-sialyltransferase in normal human leukocytes and increased activity of this enzyme in granulocytes from chronic myelogenous leukemia patients.

We have examined granulocytes from patients with chronic myelogenous leukemia (CML) and from normal subjects to determine whether activity of a specific sialyltransferase might account for the aberrant sialylation of O-linked membrane oligosaccharides in CML cells. Total membrane preparations of morphologically mature CML and normal granulocytes were tested for sialyltransferase activity using the substrates galactosyl-beta 1-3-N-acetyl-D-galactosamine-alpha-O-nitrophenyl and N-acetyl-D-galactosamine-alpha-phenyl. N-Acetyl-D-galactosamine-alpha-phenyl was not an acceptor with either CML or normal cells. With galactosyl-beta 1-3-N-acetyl-D-galactosamine-alpha-O-nitrophenyl, sialyltransferase activity was 2.8 times higher in CML cells compared to normal cells. Product identification by high performance liquid chromatography showed that enzyme from both normal and CML granulocytes linked sialic acid to galactosyl-beta 1-3-N-acetyl-D-galactosamine-R by the alpha(2-3) and not the alpha(2-6) linkage. The enzyme CMP-N-acetylneuraminic acid: galactosyl-beta 1-3-N-acetyl-D-galactosamine-R alpha(2-3)-sialyltransferase has not previously been described in human granulocytes. The marked increase in activity of this enzyme in CML and the resulting increase in sialylation may contribute to the pathophysiological behavior of CML granulocytes.

Antifreeze Proteins↗
PubMed1987

Effect of verapamil and other agents on the distribution of anthracyclines and on reversal of drug resistance.

We studied the intracellular distribution of drugs within anthracycline-sensitive and -resistant cells by computer-assisted digitized video fluorescence microscopy. We found that the antitumor antibiotic, daunorubicin, distributes differently in anthracycline-sensitive and -resistant human leukemia cells (HL-60). Verapamil and other agents known to circumvent resistance in pleiotropic drug-resistant cell lines were able to change the pattern of distribution of daunorubicin in the anthracycline-resistant HL-60 cells back to the distribution found in anthracycline-sensitive HL-60 cells. To investigate the biochemical basis for this effect, we studied the distribution of daunorubicin and doxorubicin in a hydrophobic/hydrophilic (membrane/cytoplasmic) environment using the two-compartment cell-free system of Folch. Our results demonstrate that various unrelated drugs known to overcome resistance will also change the distribution of the anthracyclines in the hydrophobic/hydrophilic compartments. Our data allow the hypothesis that various unrelated agents known to circumvent resistance may act by altering the hydrophobic/hydrophilic solubility of anthracyclines in the resistant cell.

Antibiotics, Antineoplastic↗
PubMed1986

Changes in the granulocyte membrane following chemotherapy for chronic myelogenous leukaemia.

Granulocytes from patients with chronic myelogenous leukaemia (CML) have been previously shown to have aberrant sialylation of membrane glycoproteins. We have examined the granulocytes from CML patients receiving intermittent chemotherapy to determine the relationship of the oligosaccharide changes to treatment. Compared to cells from non-leukaemic patients, granulocytes from untreated CML patients showed less adherence to nylon wool, decreased reactivity with peanut lectin, and decreased binding of the synthetic chemotactic peptide formyl-methionine-leucine-phenylalanine (FMLP). Granulocytes from CML patients treated with chemotherapy showed nylon wool adherence, peanut lectin reactivity and FMLP binding comparable to non-leukaemic cells. Chemotherapeutic agents may interfere with oligosaccharide synthesis with a resulting change in the composition of cell surface glycoconjugates.

Agglutination Tests↗
PubMed1985

Regeneration of membrane sialic acid after neuraminidase treatment of leukemic granulocytes.

Granulocytes from patients with chronic myelogenous leukemia (CML) were studied for their ability to regenerate surface sialic acid following treatment with Vibrio cholera neuraminidase (VCN) in vitro. Immediately after neuraminidase treatment, CML and normal granulocytes showed similar incorporation of radioactivity after surface labelling with sodium periodate/potassium-H3-borohydride (PI/BH3(4)). CML granulocytes treated with neuraminidase then incubated for 18 h in nutrient medium showed strikingly increased PI/BH3(4) labelling, usually greater than initial pretreatment values, consistent with a rapid reappearance of sialic acid in the cell membrane. This pattern was not seen in normal granulocytes. The aberrant regeneration of sialic acid in CML granulocytes in vitro could be inhibited by addition of 3 X 10(-6) M retinoic acid, suggesting either a direct effect on membrane glycoconjugate synthesis or an association with granulocyte differentiation.

Cell Membrane↗
PubMed1985

Increased activity of a specific sialyltransferase in chronic myelogenous leukemia.

Granulocytes from patients with chronic myelogenous leukemia (CML) are morphologically identical to their normal counterparts but show marked differences in circulation patterns and in some membrane properties. We have previously shown that there is abnormal lectin binding to CML granulocytes, and aberrant sialylation of membrane glycoproteins. To examine the changes in sialylation of CML granulocytes further, we have studied membrane preparations from CML and normal granulocytes for specific sialyltransferase activity. Because sialyltransferase enzymes are specific for the configuration of the acceptor group, enzyme activity was assayed by measuring transfer of sialic acid from CMP-14C-sialic acid to substrates of defined structure. As compared with those of normal counterparts, CML extracts catalyzed a 50% higher overall rate of sialylation of asialofetuin, a substrate possessing both N- and O-linked acceptors. Studies of enzyme specificity utilizing porcine and ovine submaxillary mucins, antifreeze glycoprotein and alpha-1 acid glycoprotein as acceptors showed that the increased sialylation by CML extracts was due primarily to substrates with the O-linked Gal beta 1----3GaINAc acceptor group. These data suggest that sialyltransferase activity is increased in CML granulocytes compared to normal granulocytes and that the increased enzyme activity is specific for O-linked Gal beta 1----3GaINAc. This enzyme activity may be directly responsible for the abnormal membrane sialylation and pathophysiological behavior of these cells.

Asialoglycoproteins↗
PubMed1985

Effects of pyrimidine antagonists on sialic acid regeneration in HL-60 cells.

Because alterations in cell membrane sialoglycoconjugates can affect the behavior of neoplastic cells, we investigated the effects of in vitro treatment with antimetabolites used in cancer therapy on the expression of membrane sialic acid in cultured HL-60 leukemic cells. In these studies, cells were incubated with Vibrio cholerae neuraminidase to remove surface sialic acid. Reappearance of membrane sialic acid during drug treatment was followed (a) by measuring changes in radioactive surface labeling of viable cells with sodium metaperiodate-sodium[3H]-borohydride, (b) by measuring the decline in accessible surface galactosyl receptor sites which occurred coincident with membrane sialic acid replacement, and (c) by measuring the incorporation of [3H]glucosamine into membrane-associated neuraminidase-labile sialic acid. We were especially interested in learning whether drugs that affect intracellular pools of cytidine triphosphate (CTP), an important nucleotide intermediate in sialylation reactions, could inhibit regeneration of membrane sialic acid. 3-Deazauridine, a competitive inhibitor of CTP synthetase, depleted CTP pools and curtailed surface membrane resialylation with little or no effect on synthesis of de novo sialic acid from precursor sugars. The addition of cytidine restored CTP pools and sialic acid regeneration. Acivicin, a glutamine antagonist, also depleted CTP pools and curtailed surface membrane resialylation. In addition, it retarded de novo synthesis of sialic acid. The addition of cytidine restored intracellular CTP pools and sialic acid regeneration. However, both cytidine and guanosine were required to restore sialic acid synthesis from precursor sugars. 1-beta-D-Arabinofuranosylcytosine, a competitive inhibitor of sialic acid synthetase and of sialyltransferase, inhibited both de novo sialic acid synthesis and membrane resialylation. Only the latter effect was reversed by the addition of exogenous cytidine. Hydroxyurea, an agent shown previously to inhibit glycoconjugate production in hamster fibroblasts, curtailed membrane resialylation and de novo synthesis of sialic acid without depleting CTP pools. Doxorubicin, at levels that caused marked arrest of cell proliferation, had no effect on sialic acid synthesis or expression on the membrane surface. These data suggest that antimetabolites, apart from their cytotoxic effects or effects on cellular growth, may directly inhibit the expression of membrane sialic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

3-Deazauridine↗