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H Lazarus

Publications and source records attributed to H Lazarus.

At least 55 records · Page 3Linked to original sources
PubMed1981

Patterns of late replication in X chromosomes of human lymphoid cells.

Two predominant patterns of late X replication were observed in both short-term and established human lymphoid cultures. One pattern was found in a minority of short-term cultured T-cell metaphases, in most lectin-stimulated B cells, and, with minor variations, in established B-cell lines. In these cells, DNA replication terminated in the distal part of the long arm of the late X. A different pattern was found in the majority of lectin-simulated T cells and in the T-cell line CCRF-CEM. These cells exhibited terminal replication in a region of the long arm of the late X that was nearer to the centromere. It is speculated that the variations in replication patterns correlate with phenotypic and functional characteristics of human lymphoid subsets.

B-Lymphocytes↗
PubMed1981

Human cell lines express multiple populations of Ia-like molecules.

Three monoclonal antibodies have been used to isolate Ia-like antigens from three human cell lines; two of which are thought to be homozygous at the HLA-D/DR locus. Complete extraction of the Ia antigens identified by one antibody leaves those recognized by the two remaining antibodies in three parallel sets of experiments, indicating that the antigenic determinants recognized by these antibodies are present on three different populations of Ia molecules from cells of single individuals. These three populations of Ia-like molecules may reflect serologic variants of the product of a single genetic locus or may represent the products of as many as three nonallelic genetic regions. Demonstration of the existence of these multiple populations of Ia-like molecules on presumed homozygous typing cells indicates that this antigenic system is much more complex than has been generally realized. Further study may clarify the relationship between HLA-D/DR type and susceptibility to a variety of diseases and ultimately lead to better matches and improved survival for allogenic transplants. Since the HLA-D region is intimately involved in regulation of the immune response and susceptibility to a variety of diseases, use of monoclonal antibodies specific for discrete Ia antigens, the only identified products of the HLA-D region, may facilitate dissection of its many biological functions.

Antibodies, Monoclonal↗
PubMed1981

Methotrexate analogues. 13. Chemical and pharmacological studies on amide, hydrazide, and hydroxamic acid derivatives of the glutamate side chain.

Carbodiimide-mediated condensation of 4-amino-4-deoxy-N10-methylpteroic acid (APA) with several alkyl, aralkyl, and aryl amines, in the presence or absence of N-hydroxysuccinimide, was employed in order to prepare new lipid-soluble bis(amide) derivatives of methotrexate (MTX) as potential prodrugs. MTX dianilide was likewise prepared, in comparable yield, from APA and L-glutamic acid dianilide via the mixed carboxylic--carbonic anhydride method. Dihydrazide and bis(N-methylhydrazide) derivatives of MTX were formed readily from MTX diethyl ester. However, reaction with hydroxylamine led to MTX gamma-monohydroxamic acid as the sole isolated product. The bis adduct appears to form, but is unstable during workup. The identity of the product was confirmed by independent mixed anhydride synthesis from APA and the gamma-monohydroxamate of L-glutamic acid. Treatment of MTX dimethyl ester with N,N-dimethylhydrazine unexpectedly yielded MTX gamma-monomethyl ester. MTX dianilide was active against L1210 leukemia in mice, with a +155% increase in life span at a dose of 160 mg/kg given ip in 10% Tween 80 on a q3d X 3 schedule. The bis(p-chlorobenzylamide), bis(p-methoxybenzylamide), and dihydrazide were also active against L1210 leukemia in vivo, but to a lesser extent than the dianilide. The gamma-monohydroxamic acid derivative showed activity (+111% ILS at 40 mg/kg) similar to that of MTX and was found to bind to a partially purified dihydrofolate reductase preparation from L1210 cells with an ID50 of 0.005 microM as compared to 0.007 microM for MTX. In vivo experiments in mice indicated that the pharmacokinetic properties of this compound and of MTX are similar but failed to demonstrate any advantage over MTX in terms of selective uptake into tumor (sc implanted P388 leukemia) or improved penetration of the central nervous system. The activities of the dianilide, bis(benzylamide), and dihydrazide derivatives in vivo are of interest in view of their low toxicity relative to MTX against cells in culture, which suggests that these derivatives are probably acting as prodrugs in the intact animal.

Amides↗
PubMed1981

Reactivity of a monoclonal antibody with human ovarian carcinoma.

A murine monoclonal antibody (OC125) has been developed that reacts with each of six epithelial ovarian carcinoma cell lines and with cryopreserved tumor tissue from 12 of 20 ovarian cancer patients. By contrast, the antibody does not bind to a variety of nonmalignant tissues, including adult and fetal ovary. OC125 reacts with only 1 of 14 cell lines derived from nonovarian neoplasms and has failed to react with cryostat sections from 12 nonovarian carcinomas.

Animals↗
PubMed1981

Fate of a common acute lymphoblastic leukemia antigen during modulation by monoclonal antibody.

Modulation of a human common acute lymphoblastic leukemia antigen (CALLA) by specific monoclonal antibody (J5) has been studied with the immune precipitation method to identify radiolabeled antigen. Surfaces of leukemic cells have been labeled using 125I both before and after modulation by J5 antibody for different time intervals. Leukemic cells have also been metabolically labeled with 35S-methionine before modulation. These studies indicate that the 100,000-dalton glycoprotein expressing CALLA (gp 100-CALLA) cannot be detected in cells that were modulated with J5 antibody before surface labeling but that it is easily detectable in cells that were surface labeled before modulation for 10 hr. At later time points, gp 100-CALLA is selectively lost from cells that were surface labeled before modulation. Gp 100-CALLA is not detected in the supernatants from cultures of these modulated cells. We conclude that gp 100-CALLA is rapidly internalized during modulation and that CALLA is degraded. Gp 100-CALLA is not shed into the culture media, nor does it remain on the cell surface in an altered form. Incubation of leukemic cells with antisera to beta2-microglobulin or IgM does not affect the expression of gp 100-CALLA.

Antibodies, Neoplasm↗
PubMed1981

Sex-related differences in tumor progression associated with altered lymphocyte circulation.

Male and female ACI rats were inoculated with the syngeneic H-4-II-E hepatoma, and the natural history of the tumor, histopathology, and lymphocyte migration were studied. The tumor formed a.s.c. mass in all 16 males and in 22 of the 26 females given injections. In the males, tumors progressed, and all animals died with the mean survival time of 54 days. Complete tumor regression was observed in all but two females. In the females, there was prominent lymphocytic infiltration of the tumor, while males had no cellular reaction at the tumor site. The regional lymph nodes in males usually contained metastases and were nonreactive. The female lymph nodes did not contain metastases but contained many lymphocytes within the peripheral sinus and sinusoids. Six male-female pairs were castrated before tumor inoculation. Castration had no effect on the natural history or the etiology of the tumor. Comparing seven normal control male-female littermate pairs, there were no differences in lymphocyte accumulation in the lymph nodes 22 hr following injection of 51Cr-labeled syngeneic lymphocytes. In seven tumor-bearing male-female littermate pairs, there was a significant decrease in lymphocyte migration to the lymph nodes (p less than 0.001) in tumor-bearing males as compared to that in both their female littermates and control males. Depressed lymphocyte circulation in the males was associated with rapid progression of tumors resulting in the death of the animals. Unimpaired lymphocyte mobilization in the tumor-bearing females was associated with complete regression in most animals.

Animals↗
PubMed1980

A monoclonal antibody to human acute lymphoblastic leukaemia antigen.

Previous studies by Greaves and others have demonstrated the existence of an antigen associated with cells from many patients with acute lymphoblastic leukaemia (ALL) and some patients with chronic myelocytic leukamemia (CML) in blast crisis. Antisera to this common ALL antigen (CALLA) have been produced in rabbits and require extensive absorption which limits both the titre and quantity of antisera that can be generated and may result in variable specificity in different laboratories. The method for generation of specific antibody by somatic cell hybridisation introduced by kohler and Milstein has been successfully used to produce monoclonal antibodies against various normal human cell-surface proteins, including beta 2 microglobulin, histocompatibility antigens, thymocyte and peripheral T-cell antigens and Ia-like antigens. The present report describes the generation and characterisation of a monoclonal antibody specific for a common ALL antigen (CALLA) previously identified by conventional heteroantisera.

Animals↗
PubMed1980

Human leukemia-associated antigen: relation to a family of surface glycoproteins.

A heteroantiserum raised to leukemic cells of a patient with non-T cell acute lymphoblastic leukemia (ALL) has been extensively absorbed with cells from a leukemic T cell line and an autologous B lymphoblastoid cell line to produce a common ALL antiserum (CALLA). CALLA is specific for leukemic cells of most patients with non-T cell ALL and chronic myelogenous leukemia (CML) in lymphoid blast crisis. It has been extensively tested on a wide variety of normal cells and is unreactive with them. CALLA identifies a surface glycoprotein having a m.w. of approximately 100,000 on reactive cell populations. In contrast, partially absorbed anti-ALL sera detect a similar glycoprotein band on CALLA-negative B and T cell lines. The glycoprotein identified by CALLA has been isolated and used as an immunogen. This new antiserum (C129) detects a 100,000-dalton glycoprotein not only on CALLA-positive cell populations but also on most CALLA-negative normal and malignant hematopoietic cells and on B and T cell lines. We conclude that there exists a family of 100,000-dalton glycoproteins that are present on a variety of normal, transformed, and malignant cells and that possess shared as well as unique antigenic regions. The expression of at least one of these antigens, detected by CALLA, may be tumor specific.

Animals↗
PubMed1979

Restriction endonuclease mapping of the human gamma globin gene loci.

The restriction endonuclease sites in and around the human gamma globin gene loci have been mapped using the gel blotting technique of Southern, in both normal DNA and DNA from an individual with hereditary persistence of fetal hemoglobin (HPFH). In normal DNA, the gamma genes are linked to the delta (and beta) globin genes, and the orientation of these genes with respect to transcription is (5') G gamma leads to A gamma leads to delta leads to beta (3'). The distance between the G gamma and A gamma genes is 3.5 kb and that between the A gamma and delta genes is 16 kb. In both normal DNA and HPFH DNA, the gamma genes are interrupted by an intervening sequence, approximately 1 kb in length that is situated between codon positions 99 and 121 of the coding sequence. In different DNA samples, there is polymorphism for the presence or absence of a Hind III site in the intervening sequence of either gamma golbin gene. In HPFH DNA, a deletion of at least 16 kb of DNA has been detected. This deletion starts at a point approximately 12.5 kb from the 3'-end of A gamma gene and extends through the delta and beta globin genes to a point at least 3 kb beyond the 3'-end of beta globin gene.

Base Sequence↗
PubMed1979

The molecular basis of alpha-thalassemias: frequent occurrence of dysfunctional alpha loci among non-Asians with Hb H disease.

Study of Asians has previously indicated that deletion of alpha-globin structural genes is the predominant lesion in alpha-thalassemias and that Hb H disease occurs when three of four normal alpha loci per cell are deleted. To test the generality of this model, Hb H disease DNAs of both Asian and non-Asian origin were analyzed by restriction endonuclease mapping using the technique of Southern (1975). Whereas in normal DNA, alpha sequences are present in a single Eco Rl fragment of cellular DNA approximately 22.5 kb long, fragments of 22.5, 20 and 2.6 kb were found in various Hb H disease DNAs. The 20 kb Eco Rl fragment alone, in which a single alpha-globin structural locus resides, was found in Asian Hb H disease DNA. This finding is consistent with the deletion model of alpha-thalassemia. In contrast, seven of eight non-Asian Hb H disease DNAs displayed a more complex molecular composition. The fragment patterns observed were 22.5 kb alone, 22.5 plus 2.6 kb, 20 plus 2.6 kb and 20 kb alone. Non-Asian Hb H disease DNAs contained one, two or three alpha loci per cell in contrast to the one locus predicted by the simple deletion model of alpha-thalassemia. The data are best explained by the existence of defective alpha loci in certain individuals with alpha-thalassemia, particularly outside the Asian population. Restriction mapping of the 20 kb Eco Rl fragment found in Asian and some non-Asian Hb H disease DNAs demonstrated a striking similarity in the placement of restriction sites about the single alpha gene compared with sites about the two genes in the 22.5 kb Eco Rl fragment seen in normal DNA. These data are consistent with origin of the 20 kb fragment from the 22.5 kb normal Eco Rl fragment by either unequal crossing-over or a deletion event. The molecular heterogeneity and frequent occurrence of defective alpha loci in non-Asian Hb H disease DNAs described here may explain, in part, the clinical heterogeneity of alpha-thalassemias and the absence of the homozygous deletion state (hydrops fetalis) in non-Asians. Further study of cellular DNA fragments containing the defective alpha loci identified in this work may indicate the types of specific mutations responsible for abnormal globin gene expression and complement similar studies on abnormal beta genes in beta-thalassemias.

Asia↗
PubMed1979

Leukemia-associated antigens in ALL.

A cytotoxic common ALL antiserum (CALLA) specific for leukemic cells of most patients with non-T-cel- acute lymphoblastic leukemia (ALL) and of some patients with chronic myelogenous leukemia (CML) in blast crisis has been reproducibly prepared using cell lines for absorption. CALLA reacts with leukemic cells of 110 of 134 patients (82%) with non-T-cell ALL; 1 of 71 (1%) patients with acute myelogenous leukemia (AML); 2 of 7 patients (29%) with chronic myelogenous leukemia in blast crisis; 7 of 92 patients (8%) with other hematologic malignancies; and with the leukemic cell lines Laz 221 and NALM-1. It does not react with the normal hematopoietic cells, B- or T-cell lines, or cells from 26 patients with T-cell ALL that were tested. CALLA reactivity and periodic acid Schiff (PAS) staining correlate poorly, with CALLA reacting with cells from 86% (64 of 74) of patients with PAS-positive and 76% (29 of 38) of those with PAS-negative non-T-cell ALL. In these patients, CALLA reacts with cells from 89% of those under age 12 (78 of 88); 74% of those aged 12--20 (20 of 27); and 58% of those over 20 (11 of 19). Using only CALLA and antisera specific for Ia-like and T-cell antigens, we can now distinguish most cases of ALL from AML and other hematologic malignancies.

Absorption↗
PubMed1979

L-cyst(e)ine requirements of malignant cells and progress toward depletion therapy.

The L-cyst(e)ine requirements of normal and malignant cells are reviewed and expanded within the context of establishing whether the measurement of gamma-cystathionase levels constitutes a predictive test for tumor sensitivity to L-cyst(e)ine depletion. The ability of both purified L-cysteine desulfhydrase and gamma-cystathionase to inhibit the growth of the L-cystine-dependent L1210 leukemia in culture is presented, as well as approaches to circumvent the limitations of these enzymes for in vivo therapy. The ability of proparagylglycine to inhibit L-cysteine biosynthesis in vivo is reviewed for its possible use in combination therapy. In addition, the ability of poly D,L-alanine modification of Escherichia coli L-asparaginase to increase the plasma half-life in mice tenfold as well as to decrease the immunogenicity of the enzyme is presented.

Animals↗