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Biomedical subjects

S M Luger

Publications and source records attributed to S M Luger.

24 records · Page 2Linked to original sources
PubMed1992

In vivo treatment of human leukemia in a scid mouse model with c-myb antisense oligodeoxynucleotides.

The c-myb protooncogene encodes proteins that are critical for hematopoietic cell proliferation and development. Disrupting c-myb function might, therefore, prove an effective therapeutic strategy for controlling leukemic cell growth. Antisense oligodeoxynucleotides have been utilized for this purpose in vitro, but their in vivo efficacy has not been reported. We therefore established human leukemia-scid mouse chimeras with K562 cells and treated diseased animals with phosphorothioate-modified antisense oligodeoxynucleotides. K562 cells express the c-myb protooncogene, which served as the target for the antisense DNA. They also express the tumor-specific bcr-abl oncogene that was utilized to track the human cells in the mouse host. Once circulating leukemic blast cells had been detected, the survival of untreated control mice was 6 +/- 3 days (mean +/- SD). The survival of animals treated for 7 or 14 days with either sense or scrambled-sequence c-myb oligodeoxynucleotides was not statistically different from the control animals. In distinct contrast, animals treated for similar lengths of time with antisense c-myb oligodeoxynucleotides survived at least 3.5 times longer than the various control animals. In addition, animals receiving antisense c-myb DNA had significantly less disease at the two sites most frequently manifesting leukemic cell infiltration, the central nervous system and the ovary. These results suggest that phosphorothioate-modified antisense DNA may be efficacious for the treatment of human leukemia in vivo, and by analogy, for the treatment of other human neoplasias.

Animals↗
PubMed1992

Acute- and chronic-phase chronic myelogenous leukemia colony-forming units are highly sensitive to the growth inhibitory effects of c-myb antisense oligodeoxynucleotides.

We have previously demonstrated that malignant hematopoietic colony-forming units (CFUs) may be purged from normal CFU by exposure to c-myb antisense oligodeoxynucleotides (oligomers). This novel strategy appeared particularly promising for patients with chronic myelogenous leukemia (CML) in blast crisis, since in some cases complete elimination of bcr-abl-expressing cells was accomplished. We have examined 11 additional patients, including seven in chronic phase, in order to extend these initial observations. We sought in particular to determine if elimination of bcr-abl-expressing clones was a usual event. Exposure of CML cells to c-myb antisense oligomers resulted in inhibition of CFU-granulocyte, macrophage (CFU-GM)-derived colony formation in eight of 11 (73%) cases evaluated. Inhibition was antisense sequence-specific, dose-dependent, ranged between 58% and 93%, and was statistically significant (P less than or equal to .03) in seven of the eight cases. In two cases, CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM)-derived colony formation was also examined and found to be inhibited by the c-myb antisense oligomers in a sequence-specific manner. To determine whether CML CFU had been reduced or eliminated after exposure to the antisense oligomers, we examined cells in the residual colonies for bcr-abl mRNA expression using a reverse transcription-polymerase chain reaction detection technique (RT-PCR). Eight cases were evaluated and in each case where antisense myb inhibited growth, bcr-abl expression as detected by RT-PCR was either greatly decreased or nondetectable. No residual leukemic CFU were demonstrable on replating of treated cells. These results suggest that c-myb antisense oligomers substantially inhibit the growth and survival of CML CFU in both chronic and blast phase of disease. They may therefore prove useful for both ex vivo and in vivo treatment of CML.

Actins↗
PubMed1992

Role of the KIT protooncogene in normal and malignant human hematopoiesis.

The role of the KIT protooncogene in human hematopoiesis is uncertain. Therefore, we examined KIT mRNA expression in normal human bone marrow mononuclear cells (MNC) and used antisense oligodeoxynucleotides (oligomers) to disrupt KIT function. KIT mRNA was detected with certainty only in growth factor-stimulated MNC. Expression was essentially abrogated by making MNC quiescent or by inhibiting myb gene function. Oligomers blocked KIT mRNA expression in a dose-response and sequence-specific manner, thereby allowing functional examination of the KIT receptor. In experiments with either partially purified or CD34(+)-enriched MNC, neither granulocyte nor megakaryocyte colony formation was inhibited by oligomer exposure. In contrast, KIT antisense oligomers inhibited interleukin 3/erythropoietin-driven erythroid colony formation approximately 70% and "stem cell factor"/erythropoietin-driven colony formation 100%. The presence of erythroid progenitor cell subsets with differential requirements for KIT function is therefore suggested. Growth of hematopoietic colonies from chronic myeloid leukemia and polycythemia vera patients was also inhibited, while acute leukemia colony growth appeared less sensitive to KIT deprivation. These results suggest that KIT plays a predominant role in normal erythropoiesis but may be important in regulating some types of malignant hematopoietic cell growth as well. They also suggest that KIT expression is linked to cell metabolic activity and that its expression may be regulated by or coregulated with MYB.

Antigens, CD↗
PubMed1992

The c-kit proto-oncogene in normal and malignant human hematopoiesis.

The c-kit proto-oncogene encodes a tyrosine kinase receptor (KIT) which is expressed on many types of human cells. Numerous studies attest to the importance of the c-kit receptor and its ligand, known variously as stem cell factor (SCF), mast cell growth factor (MGF), Steel factor (SF), or kit ligand (KL) (the nomenclature we prefer), in the development of human hematopoietic cells. KL, which is produced in membrane-bound and soluble forms by bone marrow stromal cells, acts on pre-colony forming units (pre-CFU) and CFU cells. In synergistic combination with other cytokines, KL enhances the growth of myeloid progenitor cells. However, using an antisense oligodeoxynucleotide strategy to disrupt c-kit function, we have demonstrated that the KL-KIT complex is of greatest importance for generation and/or proliferation of normal human erythropoietic progenitor cells. In malignant hematopoietic cells, the complex also appears to be important for growth of granulocyte/macrophage (GM) CFU as well.

Amino Acid Sequence↗
PubMed1986

Role of ribosome degradation in the death of starved Escherichia coli cells.

In Escherichia coli cultures limited for phosphate, the number of ribosomal particles was reduced to a small percentage of its earlier peak value by the time the viable cell count began to drop; the 30S subunits decreased more than the 50S subunits. Moreover, the ribosomal activity was reduced even more: these cells no longer synthesized protein, and their extracts could not translate phage RNA unless ribosomes were added. The translation initiation factors also disappeared, suggesting that they become less stable when released from their normal attachment to 30S subunits. In contrast, elongation factors, aminoacyl-tRNA synthetases, and tRNA persisted. During further incubation, until viability was reduced to 10(-5), the ribosomal particles disappeared altogether, while tRNA continued to be preserved. These results suggest that an excessive loss of ribosomes (and of initiation factors) may be a major cause of cell death during prolonged phosphate starvation.

Bacterial Proteins↗