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Biomedical subjects

J Whang-Peng

Publications and source records attributed to J Whang-Peng.

At least 19 recordsLinked to original sources
PubMed1992

Cytogenetic studies in subgroups of rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and accounts for 10% of all solid tumors in children. There are three different histologic forms of this tumor: embryonal (RMS-E), alveolar (RMS-A), and primitive (RMS-P). Among these, the embryonal form has responded well to chemotherapy. Identification of the correct subtype is important for both the management and treatment of this malignancy. However, the histopathologic classification of RMS is sometimes difficult and distinguishing between the embryonic and primitive forms can present a diagnostic dilemma. Chromosomal abnormalities have been observed in all subtypes. We present the cytogenetic findings in six cases of RMS or related sarcoma. All four cases with RMS-A had both numerical and structural abnormalities in the tumor and involved bone marrow specimens. Three patients had a common marker, t(2;13)(q37;q14), and one patient had a variant marker involving 13q14, t(1;13) (p36;q14), and double minutes (dmin). The single embryonal RMS patient had modal chromosome numbers in the hypertriploid range and extensive structural abnormalities; the t(2;13) was not present, but translocation of 13q to both 1q and 2p was observed, der(1)t(1;13)(q21;q14) and der(2)t(2;13)(p25;q14). The patient with primitive type RMS had a hypodiploid line with several markers, including a complex translocation involving chromosomes 5 and 13 with a breakpoint at 13q14, and t(11;12)(q24;q12), a chromosome marker heretofore found only in Ewing's sarcoma and related tumors. This patient had atypical RMS with mixed neural and myogenic elements. The significance of these chromosomal markers and their importance in the characterization of childhood tumors are discussed, along with a review of the literature.

Adolescent↗
PubMed1992

T-cell lymphoblastic lymphoma with eosinophilia associated with subsequent myeloid malignancy.

Three patients with T-cell lymphoblastic lymphoma and peripheral blood eosinophilia are reported. At the time of diagnosis, all patients had lymphadenopathy, and one had a mediastinal mass. Lymph node biopsies revealed lymphoblastic lymphoma admixed with a variable number of mature eosinophils. Immunophenotypic studies demonstrated that each lymphoma had an immature T-cell immunophenotype. Bone marrow biopsies were hypercellular with myeloid hyperplasia and eosinophilia but were negative for lymphoma. All patients received multiagent chemotherapy; one patient achieved a complete remission, and two patients had partial remissions. All patients subsequently developed a myeloid malignancy. Two died of acute myeloid leukemia within 18 months of the diagnosis of lymphoblastic lymphoma. The third patient relapsed with a lymphoma that had histologic and immunophenotypic features of both T-cell lymphoblastic lymphoma and granulocytic sarcoma and also developed a poorly defined myeloproliferative disorder. These findings suggest that T-cell lymphoblastic lymphoma associated with eosinophilia may represent a distinct clinico-pathologic entity with a high risk of subsequent myeloid neoplasia.

Acute Disease↗
PubMed1992

Hereditary and acquired p53 gene mutations in childhood acute lymphoblastic leukemia.

The p53 gene was examined in primary lymphoblasts of 25 pediatric patients with acute lymphoblastic leukemia by the RNase protection assay and by single strand conformation polymorphism analysis in 23 of 25 cases. p53 mutations were found to occur, but at a low frequency (4 of 25). While all four mutations were identified by single strand conformation polymorphism, the comparative sensitivity of RNase protection was 50% (2 of 4). Heterozygosity was retained at mutated codons in 3 of 4 cases. One pedigree was consistent with the Li-Fraumeni syndrome, and bone marrow from both diagnosis and remission indicated a germline G to T transversion at codon 272 (valine to leucine). Although members of another family were affected with leukemia, a 2-bp deletion in exon 6 was nonhereditary. The other two nonhereditary p53 mutations included a T to G transversion at codon 270 (phenylalanine to cysteine) and a G to C transversion at codon 248 (arginine to proline). These data support the role of both hereditary and acquired p53 mutations in the pathogenesis and/or progression of some cases of childhood acute lymphoblastic leukemia.

Adolescent↗
PubMed1992

Absence of hereditary p53 mutations in 10 familial leukemia pedigrees.

Germline p53 mutations have been identified in the Li-Fraumeni syndrome but the role of such mutations in familial leukemia is not established. The p53 gene was examined by single-strand conformation polymorphism analysis of exons 4-8 in 10 families with multiple members affected with leukemia. The diagnoses included acute and chronic leukemias and Hodgkin's disease. Identified in two families were p53 mutations that were nonhereditary. These included a 2-bp deletion in exon 6 found in the lymphoblast DNA of one child whose sibling, cousin, and several adult relatives had acute leukemia. The other nonhereditary p53 mutation was a transition at codon 248 (CGG to CAG, arginine to glutamine) found in the lymphoblasts of a patient with a preleukemic syndrome and acute lymphoblastic leukemia (ALL) whose brother is a long-term survivor of ALL. Thus, p53 mutations were found to occur in two families but both were nonhereditary. Moreover, in the remaining eight families no p53 mutation was identified in the regions of p53 where most mutations have been found in other cancers. Although p53 mutations sometimes may be present, they do not appear to be a primary event responsible for hereditary susceptibility to familial leukemia. This study suggests involvement of other genes or mechanisms.

DNA, Neoplasm↗
PubMed1991

Nonrandom structural and numerical chromosome changes in non-small-cell lung cancer.

Cytogenetic studies were performed on 27 tumor cell lines (most of which were derived from metastatic lesions) and four fresh malignant pleural and pericardial effusions from 30 patients with non-small-cell lung cancer (non-SCLC). Many clonal structural (deletions and nonreciprocal translocations) and numerical abnormalities were found in each specimen. Statistical analysis revealed these changes were nonrandomly distributed among the chromosomes. A statistically significant number of chromosomal breakpoints were seen in regions 1q1, 1q3, 3p1, 3p2, 3q1, 3q2, 7q1, 13p1, 14p1, 15p1, and 17q1 when the regions were compared to the total haploid complement. In addition, when a given region was compared to other regions within the same chromosome, statistically significant numbers of breakpoints were noted for regions 1q3, 5q1, 7q1, 13p1, 14p1, 15p1, 16q2, 17q1, and 21p1. Specific chromosome bands showing the most frequent involvement in structural abnormalities were (in descending order) 3p14.2, 3q21, 19q13, 11p15, 1q11, 7q11, 1q21, 3p23, and 3p21. The breakpoints indicate areas to look for new dominant oncogenes activated by translocations, while the areas of deletions and loss of material by nonreciprocal translocations highlight areas to search for recessive oncogenes. These cytogenetic studies represent strong evidence that multiple genetic lesions are associated with the development of metastatic lung cancer, and provide a roadmap to search for new genes involved in the pathogenesis of lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1990

Induction of topoisomerase II gene expression in human lymphocytes upon phytohemagglutinin stimulation.

The carboxyl-terminal one-third of human topoisomerase II polypeptide expressed in Escherichia coli was used as antigen to generate polyclonal antibodies in rabbits. With the use of antiserum, DNA topoisomerase II levels of phytohemagglutinin-stimulated human lymphocytes were measured by immunoblotting. Our results showed that the increase in intracellular topoisomerase II level paralleled the entry of cells into proliferation. We also found that the increase in the topoisomerase II level resulted from an increase in the amount of topoisomerase II mRNA. The time course study indicated that the appearance of topoisomerase II mRNA was first observed at 36 h after phytohemagglutinin stimulation. The maximal level of topoisomerase II mRNA was seen at 45 h after stimulation. The same RNA blot was rehybridized with a thymidine kinase probe. The maximal level of thymidine kinase mRNA was observed at 39 h after phytohemagglutinin stimulation. In a comparison of the time course of topoisomerase II gene expression with that of [3H]thymidine incorporation and thymidine kinase gene expression, it was found that the expression of the topoisomerase II gene was later than the onset of DNA replication. Thus, this study suggests that topoisomerase I, which is constantly expressed throughout the cell cycle, might participate in the initiation of DNA replication, while topoisomerase II is involved in solving the DNA topological problems accompanying DNA strand separation during DNA replication.

Cells, Cultured↗
PubMed1990

Cytogenetic studies of esophageal carcinoma cell lines.

Although the incidence of cancer of the esophagus is low in the United States, the prognosis of patients with this malignancy is poor, especially when metastases exist. More research concerning the biological characteristics of this tumor is necessary to permit more effective treatment and to determine the etiology. We successfully studied cytogenetically 14 short- and long-term cell lines derived from esophageal carcinoma to determine whether these tumors have nonrandom, unique chromosomal abnormalities. Our results showed that the tumor cells had chromosome numbers clustering around a modal number that varied according to the cell line. The presence in the primary explant of extensive numerical and structural abnormalities involving every chromosome including the sex chromosomes indicate that these abnormalities occur early in the malignant cells. The chromosomes most frequently involved in the structural abnormalities were 1, 9, and 11, each occurring in 13 of the 14 lines, and of three found in 12 of the 14 lines. The major aberrations resulted in deletions of portions of these chromosomes. The most frequent breakpoints for these abnormalities occurred at 3p14, 11q11q12; and 9q11q12 as well as in the centromeric regions of all the acrocentric chromosomes. Another unusual chromosomal marker found in three lines (HCE-1, HCE-3, and HCE-5) was a homogeneously staining region (HSR) that occurred as an extension on 11q12.

Adult↗
PubMed1989

Retention of chromosome 3 in extrapulmonary small cell cancer shown by molecular and cytogenetic studies.

In small cell lung carcinoma, one of the short arms of chromosome 3 is typically lost. To investigate chromosome 3 in extrapulmonary small cell carcinoma, we used DNA probes that detect restriction-fragment-length polymorphisms at loci on 3p. These probes were used to study DNA extracted from tumors and normal tissues and/or tumor cell lines from five patients with extrapulmonary small cell cancer. Tumor DNA from four of the five patients with extrapulmonary small cell cancer retained heterozygosity at loci on 3p. Cytogenetic studies of the tumor cell lines established from these four patients showed retention of both short arms of chromosome 3. We conclude that the loss of genetic material from 3p observed in small cell lung cancer is not typical in extrapulmonary small cell cancer.

Adult↗
PubMed1989

Cytogenetic studies of 21 patients with acute lymphoblastic leukemia in relapse.

Karyotypes of 21 patients, originally entered into the Third International Workshop on Chromosomes in Leukemia (3IWCL), were investigated in first, second and/or subsequent relapses. Karyotypes at diagnosis were related to the relapses in the following ways: normal to normal (N-N) (five cases); abnormal to normal (A-N) (two cases); abnormal to abnormal with no change (A-A) (five cases); abnormal to abnormal with clonal evolution (A-A+) (eight cases); and normal to abnormal (N-A) (one case). The A-A group comprised two each of t(4;11) and t(9;22) cases and one pseudodiploid case; included in this group were the only two patients who did not receive intensive treatment. Both A-N cases had been pseudodiploid at diagnosis. Clonal evolution A-A+ occurred in patients who had had 47-49 chromosomes or pseudodiploidy at diagnosis and was mainly due to the addition of structural change. The additional abnormalities were different in each case. The only de novo appearance of a clone (N-A) was in host cells in relapse following bone marrow transplantation. Clonal evolution occurred in patients who had been intensively treated and who relapsed late; the median time from diagnosis to relapse studied for the A-A group was 6 months and for the A-A+ group was 24 months. Survival following relapse was shorter for patients who had had a clonal abnormality at any time (median 10 months) than for those with no abnormality at diagnosis or in relapse (median 26 months).

Adolescent↗
PubMed1989

Studies of topoisomerase-specific antitumor drugs in human lymphocytes using rabbit antisera against recombinant human topoisomerase II polypeptide.

A complementary DNA fragment of the human DNA topoisomerase II gene was cloned into a T7 expression vector and overproduced in Escherichia coli. Rabbit polyclonal antibodies were raised against the recombinant topoisomerase II polypeptide which corresponds to the C-terminal one-third of human topoisomerase II polypeptide. Using the antiserum, DNA topoisomerase II levels were measured by immunoblotting human lymphocytes following phytohemagglutinin (PHA) stimulation. Our results showed that the intracellular topoisomerase II but not the topoisomerase I level increased in parallel with the entry of cells into proliferation. At least a 100-fold increase in topoisomerase II was observed at 50 h after PHA stimulation. As topoisomerase II levels increased upon PHA stimulation, DNA damage induced by teniposide (VM26) increased in parallel, as measured by both DNA synthesis inhibition and chromosomal aberrations. However, the damage induced by camptothecin also increased upon PHA stimulation, while the level of topoisomerase I remained relatively constant. Our results suggest that, in addition to cellular contents of topoisomerases, the state of cell proliferation is another important determinant of drug action.

Animals↗
PubMed1988

Structure of the human neutrophil elastase gene.

The gene for human neutrophil elastase (NE), a powerful serine protease carried by blood neutrophils and capable of destroying most connective tissue proteins, was cloned from a genomic DNA library of a normal individual. The NE gene consists of 5 exons and 4 introns included in a single copy 4-kilobase segment of chromosome 11 at q14. The coding exons of the NE gene predict a primary translation product of 267 residues including a 29-residue N-terminal precursor peptide and a 20-residue C-terminal precursor peptide. Analysis of the N-terminal peptide sequence suggests it contains a 27-residue "pre" signal peptide followed by a "proN" dipeptide, similar to that of other blood cell lysosomal proteases. The sequences for the mature 218-residue NE protein are included in exons II-V. The 5'-flanking region of the gene includes typical TATA, CAAT, and GC sequences within 61 base pairs (bp) of the cap site. The sequence 1.5 kilobases 5' to exon I contains several interesting repetitive sequences including six tandem repeats of unique 52- or 53-bp sequences. The 5'-flanking region also contains a 19-bp segment with 90% homology to a segment of the 5'-flanking region of the human myeloperoxidase (MPO) gene, a gene also expressed in bone marrow precursor cells and a protein stored in the same neutrophil granules as NE. In addition, like the MPO gene, the NE 5'-flanking region has several regions with greater than or equal to 75% homology to sequences 5' to c-myc, but there is no overlap between the NE-c-myc and MPO-c-myc homologous sequences.

Amino Acid Sequence↗
PubMed1988

Deletion of 3(p14p23) in secondary erythroleukemia arising in long-term survivors of small cell lung cancer.

Cytogenetic studies were done on the leukemia cells of two patients with small cell lung cancer (SCLC) who developed erythroleukemia (acute nonlymphocytic leukemia, French-American-British M6) after combined modality chemotherapy and radiotherapy for their lung cancer. Surprisingly, both erythroleukemias exhibited the del(3)(p14p23) predominantly found in SCLC. In four other patients who had secondary erythroleukemias associated with other cancers, no deletions of 3p were found. These findings could be accounted for by one of three possible mechanisms: (a) an inherited recessive gene (anti-oncogene or tumor suppressor gene) in this region of 3p was uncovered by the combined modality therapy, (b) an inherited predisposition to damage of both chromosomes at 3p14 leads to SCLC and erythroleukemia after exposure to carcinogens and/or chemotherapy-radiotherapy, or (c) the finding of lineage specificity for the 3p deletion with the presence of the 3p deletion in SCLC and erythroleukemia suggests a common bone marrow precursor.

Aged↗
PubMed1988

Establishment of human mesothelioma cell lines (MS-1, -2) and production of a monoclonal antibody (anti-MS) with diagnostic and therapeutic potential.

We have established and characterized two mesothelioma cell lines, MS-1 and MS-2, in four attempts at long-term culture of these cells. Both MS-1 and MS-2 cells consistently express cytokeratin and vimentin, and both have long, slender microvilli. The cells that grew indefinitely (MS-1, MS-2) had a higher DNA index and a higher nucleus:cytoplasm ratio than did those cells that failed to grow (MS-3, MS-4). All mesothelioma cells, both in short- and in long-term culture, responded to phorbol ester induction by displaying morphological differentiation, such as an increase in the number of microvilli. The distribution of vimentin and cytokeratin in the cells, however, remained the same regardless of the growth pattern or the phorbol-ester treatment of the cells. We have used MS-1 cells to produce a monoclonal antibody (anti-MS) that reacts with mesothelioma cells, but rarely with reactive or normal mesothelial cells or with cells of normal tissues. The antibody does not induce the modulation of antigen, and it causes no direct or complement-mediated cytotoxicity of MS-1 or MS-2 cells. If a toxin or an isotope conjugate of the antibody is used, it may be valuable in the near future to test it for use in immunoimaging or immunotherapy.

Antibodies, Monoclonal↗
PubMed1988

Human glutathione S-transferases. The Ha multigene family encodes products of different but overlapping substrate specificities.

The human glutathione S-transferase cDNAs encoding subunits 1 and 2 contain intrinsic ribosome-binding sites in their 5'-untranslated regions for direct expression in Escherichia coli. We show that functional human GSH S-transferases 1-1 and 2-2 are synthesized from lambda gt11 cDNA clones lambda GTH1 and lambda GTH2 in phage lysates of E. coli Y1090, in lysogens of E. coli Y1089, and from the plasmid expression constructs in pKK223-3. The E. coli-expressed human GHS S-transferases 1-1 and 2-2 do not have blocked N termini in contrast to those directly purified from human livers. These two isozymes, with 11 amino acid substitutions between them, are similar in their Km values for GSH and 1-chloro-2,4-dinitrobenzene and Kcat values for this conjugation reaction. The human GSH S-transferase 2-2, however, is a more active GSH peroxidase than transferase 1-1 toward cumene hydroperoxide and t-butyl hydroperoxide. Our results indicate that different members of a GSH S-transferase gene family with limited amino acid substitutions have different with limited amino acid substitutions have different but overlapping substrate specificities. We propose that accumulation of single amino acid replacements may be an important mechanism for generating diversity in GSH S-transferases with various xenobiotic substrates. In situ chromosomal hybridization results show that the GSH transferase Ha genes are located in the region of 6p12.

Base Sequence↗
PubMed1988

Abnormalities in structure and expression of the human retinoblastoma gene in SCLC.

Small cell lung cancer (SCLC) has been associated with loss of heterozygosity at several distinct genetic loci including chromosomes 3p, 13q, and 17p. To determine whether the retinoblastoma gene (Rb) localized at 13q14, might be the target of recessive mutations in lung cancer, eight primary SCLC tumors and 50 cell lines representing all major histologic types of lung cancer were examined with the Rb complementary DNA probe. Structural abnormalities within the Rb gene were observed in 1/8 (13%) primary SCLC tumors, 4/22 (18%) SCLC lines, and 1/4 (25%) pulmonary carcinoid lines (comparable to the 20 to 40% observed in retinoblastoma), but were not detected in other major types of lung cancer. Rb messenger RNA expression was absent in 60% of the SCLC lines and 75% of pulmonary carcinoid lines, including all samples with DNA abnormalities. In contrast, Rb transcripts were found in 90% of non-SCLC lung cancer lines and in normal human lung. The finding of abnormalities of the Rb gene in SCLC and pulmonary carcinoids (both neuroendocrine tumors) suggests that this gene may be involved in the pathogenesis of a common adult malignancy.

Carcinoma, Non-Small-Cell Lung↗
PubMed1988

Sister chromatid exchanges, chromosomal aberrations, and cytotoxicity produced by antitumor topoisomerase II inhibitors in sensitive (DC3F) and resistant (DC3F/9-OHE) Chinese hamster cells.

4'-(9-Acridinylamino)methanesulfon-m-anisidide, etoposide, and 2-methyl-9-hydroxyellipticinium are antitumor topoisomerase II (topo II) inhibitors. The relationship between drug-induced sister chromatid exchanges (SCEs) or chromosomal aberrations and cytotoxicity was investigated in Chinese hamster cells sensitive (DC3F) and resistant (DC3F/9-OHE) to topo II inhibitors. Thirty-min drug treatments produced SCEs and chromosomal aberrations in sensitive (DC3F) cells, 4'-(9-acridinylamino)methanesulfon-m-anisidide being more potent than etoposide or 2-methyl-9-hydroxyellipticinium at equimolar concentrations. Comparable treatments of resistant (DC3F/9-OHE) cells did not produce chromosomal damage. The cytotoxicity of 4'-(9-Acridinylamino)-methanesulfon-m-anisidide was also greater than that of etoposide or 2-methyl-9-hydroxyellipticinium in DC3F cells, and no cytotoxicity was observed in DC3F/9-OHE at drug concentrations that produced more than two logs of cell kill in DC3F cells. A plot of cytotoxicity versus SCEs showed a good correlation between the two parameters. Therefore, short treatments of mammalian cells with topo II inhibitors produce reversible topo II-mediated DNA breaks which are associated with chromosomal aberrations and SCEs whose number correlates with cytotoxicity. In addition, topo II mutant DC3F/9-OHE cells were more sensitive than DC3F cells to the chromosomal, DNA cross-linking and cytotoxic effects of mitomycin C and were equally sensitive to the cytotoxic effect of camptothecin.

Amsacrine↗