Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability to clone primary tumors in soft agar has proven useful in the study of the kinetics and biological properties of tumor stem cells. We report the development of an in vitro assay which permits formation of colonies of human monoclonal plasma cells in soft agar. Colony growth has been observed from bone marrow aspirates from 75% of the 70 patients with multiple myeloma or related monoclonal disorders studied. Growth was induced with either 0.02 ml of human type O erythrocytes or 0.25 ml of medium conditioned by the adherent spleen cells of mineral oil-primed BALB/c mice. 5-500 colonies appeared after 2-3 wk in culture yielding a plating efficiency of 0.001-0.1%. The number of myeloma colonies was proportional to the number of cells plated between concentrations of 10(5)-10(6) and back-extrapolated through zero, suggesting that colonies were clones derived from single myeloma stem cells. Morphological, histochemical, and functional criteria showed the colonies to consist of immature plasmablasts and mature plasma cells. 60-80% of cells picked from colonies contained intracytoplasmic monoclonal immunoglobulin. Colony growth was most easily achieved from the bone marrow cells of untreated patients or those in relapse. Only 50% of bone marrow samples from patients in remission were successfully cultured. Tritiated thymidine suicide studies provided evidence that for most myeloma patients, a very high proportion of myeloma colony-forming cells was actively in transit through the cell cycle. Velocity sedimentation at 1 g showed myeloma stem cells sedimented in a broad band with a peak at 13 mm/h. Antibody to granulocyte colony-stimulating factor did not reduce the number or size of the colonies. Increased numbers of myeloma colonies were seen when the marrow was depleted of colony-stimulating factor elaborating adherent cells before plating. This bioassay should prove useful in studying the in vitro biological behavior of certain bone marrow-derived (B)-cell neoplasia. In addition, systematic and predictive studies of anticancer drug effects on myeloma stem cells should now be feasible.
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PMID:Primary bioassay of human myeloma stem cells. 30 65

We demonstrate here that the functional ornithine decarboxylase (ODC) gene of alpha-difluoromethylornithine (alpha-DFMO, a suicide inhibitor of ODC) resistant mouse myeloma 653-1 cells has been rearranged with the immunoglobulin heavy chain locus in a c-myc like manner. Structural analysis of a molecular clone representing this gene revealed that it is joined in a head to head configuration to the switch region of the gamma 1 immunoglobulin gene. Comparison of this rearranged ODC gene to a germline ODC gene isolated from mouse liver DNA revealed identity in the region downstream to the breakpoint which was mapped to position -1371 +/- 1 relative to the transcription initiation site (position +1). In the switch region of the gamma 1 immunoglobulin gene the breakpoint falls within a 49 bp repeat, in a sequence frequently involved in class switching. This finding further supports the notion that in B cells the immunoglobulin gene clusters are prone to random rearrangements which under selection for a tumorigenic phenotype involve oncogenes. However, as demonstrated here, employment of specific pharmacological selection can reveal rearrangements with non-oncogenic genes.
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PMID:Rearrangement between ornithine decarboxylase and the switch region of the gamma 1 immunoglobulin gene in alpha-difluoromethylornithine resistant mouse myeloma cells. 250 Oct 85

As a result of the striking discrepancy between the substantial amount of information on the role of natural killer (NK) cells derived from in vitro experimentation and the corresponding lack of data demonstrating their physiologic relevance, we have examined the importance of NK cells for the steady state production of hematopoietic stem and progenitor cells in situ. B6D2F1 mice received two 0.2-ml injections of ascites containing anti-NK 1.1 monoclonal antibody (anti-NK) directed to murine NK cells. Another group was treated similarly but received "control" ascites (CA) that was induced solely by injection of a mouse myeloma cell similar to the fusion partner of the NK 1.1 hybridoma. Two days after the last injection, we determined the number and cycling fraction (i.e., percentage of cells in S-phase determined by in vivo hydroxyurea suicide) of femoral stem cells (spleen colony-forming units; CFU-S) and committed granulocyte-macrophage (granulocyte-macrophage colony-forming units; CFU-GM), megakaryocytic (megakaryocyte colony-forming units; CFU-Meg), and erythroid (erythroid burst-forming units; BFU-E and erythroid colony-forming units; CFU-E) progenitor cells. The striking finding was the almost complete abolishment of the proliferation of CFU-Meg in the anti-NK group, resulting in a statistically significant (p less than 0.02) decrease in number to 37% of the CA control. In contrast, the cycling fraction of BFU-E was significantly (p less than 0.05) increased to 205% of the CA control with no increase in number. The number and cycling fraction of CFU-S, CFU-GM, and CFU-E in the anti-NK group were not significantly different from values in the control group. These findings add a novel aspect to the understanding of hematopoietic regulation by providing the first evidence for a differential effect of NK cells on the steady-state proliferation of CFU-Meg and BFU-E in situ.
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PMID:Differential effect of natural killer cells on modulating CFU-Meg and BFU-E proliferation in situ. 280 34

The antigen-binding receptor of helper T cells was studied by radioactive antigen-caused suicide in vitro. Purified antibodies to immunoglobulin variable regions, obtained from sera of rabbits immunized with isolated VH and VL fragments of mouse myeloma proteins (MOPC 315, XRPC 25), were used to inhibit the binding of radiotoxic antigen. Anti-VH, but not anti-V lambda or anti-V chi inhibited suicide of carrier-primed cells.
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PMID:Antibodies to immunoglobulin heavy chain variable regions protect helper cells from specific suicide by radiolabeled antigen. 615 44

Ninety-seven patients with multiple myeloma evaluated serially had both a tritiated thymidine labeling index of bone marrow plasma cells (LI%) and in vitro myeloma stem cell culture performed. Thirty-three patients with myeloma colony growth had in vitro drug sensitivity testing carried out, 18 having in addition in vitro thymidine suicide determinations. The LI% and the likelihood of in vitro myeloma colony growth were highly correlated: the higher the LI%, the more likely was colony or cluster growth (p less than 0.001). The tritiated thymidine suicide of myeloma stem cells was usually very high. There was excellent correlation between in vitro and in vivo drug sensitivity. Both pretreatment drug resistance and selective sensitivity (e.g., interferon, bisantrene, methotrexate, vinblastine) at the time of relapse were accurately detected and correlated well with survival duration (p = 0.01 Wilcoxan). Although LI% and in vitro sensitivity were clearly independent variables, a high LI% (greater than 3%) plus in vitro resistance were associated with a subsequent survival duration of less than 6 mo. The studies allowed dissection of the complex interrelationship between cell kinetics and drug sensitivity.
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PMID:Human myeloma in vitro colony growth: interrelationships between drug sensitivity, cell kinetics, and patient survival duration. 683 Oct 55

Human myeloma stem cells were detected by their capacity to form colonies in culture. Cells separated from aspirated marrow were cultured for 10 days in semi-solid methylcellulose with medium conditioned by T lymphocytes stimulated by phytohaemagglutinin (PHA-TCM). The colonies formed consisted mostly of lymphoplasmacytoid cells or plasma cells, and the immunoglobulins in the patients' myeloma cells were demonstrated also in the cytoplasm of the colony cells. The number of colonies were proportional to the number of cells plated and to the concentration of PHA-TCM. When the proportion of proliferating colony-forming units of multiple myeloma (CFU-MM) was studied using the (3H)-dT-suicide technique, the high-specific-activity (3H)-dT killed 21-45% of the CFU-MM in 7 myeloma patients. According to a single dose of Co-y-irradiation, the mean doses for impairment of regeneration (Do) were 1.00 and 1.63 Gy in 2 cases, the extrapolation numbers being 1.6 and 2.0.
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PMID:Proliferative state and radiosensitivity of human myeloma stem cells. 708 54

This chapter outlines our development of an in vitro soft agar assay for detection of human myeloma colony-forming cells. Growth was induced with either 0.02 ml of human type O erythrocytes or 0.25 ml of medium conditioned by the adherent spleen cells of mineral-oil-primed BALB/c mice. A maximum plating efficiency of 0.1% was obtained. The number of myeloma colonies was proportional to the number of cells plated between concentrations of 105--106/ml. Morphological, histochemical, and functional criteria showed the colonies to consist of immature plasmablasts and mature plasma cells. 60%--80% of cells picked from colonies contained intracytoplasmic monoclonal immunoglobulin. Tritiated thymidine suicide studies provided evidence that for most myeloma patients, a very high proportion of myeloma colony-forming cells were actively in transit through the cell cycle. Using biophysical and immunologic studies, we were able to further characterize myeloma stem cells and obtain partial enrichment of the colony-forming cells. Increased numbers of myeloma colonies were seen when the marrow was depleted of CSF, elaborating adherent cells before plating. Antibody to granulocyte colony-stimulating factor, which did inhibit granulocyte colony formation, did not reduce the number or size of the myeloma colonies. This bioassay has subsequently served as the basis for studies of in vitro biological behavior of multiple myeloma, and for measurement of drug sensitivity. The general methodology which we first developed for myeloma appears to have general applicability not only to monoclonal plasma cell disorders, but also to many other tumor types as well. Detailed biological studies and analysis of culture conditions (similar to those we have carried out in myeloma) will no doubt prove important in understanding the biology and drug sensitivity of various forms of human cancer.
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PMID:Development of a bioassay for human myeloma colony-forming cells. 720 18

This study compared psychologic function, especially depression, in patients with advanced cancer and in sociodemographically matched, physically healthy patients who had recently attempted suicide. A companion study examined self-report of depressive symptoms; the present study relied on a semistructured interview technique. Eighty patients who were hospitalized on a research oncology ward for treatment of disseminated cancer, acute leukemia, Stage IV Hodgkin's disease, or myeloma were compared by means of the Current and Past Psychopathology Scales (CAPPS) to 80 patients hospitalized on a psychiatric unit for attempted suicide. Interviewer ratings yielded scores on eight scales characterizing each patient's psychologic adjustment during the past month and 18 scales characterizing adjustment prior to the present illness (cancer or suicide attempt). Results showed that by both self-report and observer report, cancer patients wee less depressed and anxious in the past month than the psychiatric group. Approximately one-third on the cancer patients were significantly depressed, depending on the measure used; one-seventh had experienced some suicidal ideation. Cancer patients were better adjusted in the past than the comparison group; however, the cancer patients who were presently most depressed were those who had a prior history of depression and had shown a tendency to brood. Among cancer patients who died during the study period, no correlation between severity of depression and nearness to death could be found. Findings supported use of denial of dysphoric emotions by the cancer patients, but little denial of the diagnosis or the need to accept treatment. Despite stress of advanced illness and threat to life, cancer patient's reality testing and social role performance were superior to that of the suicide attempters, and on the average they had less disturbance of affect and cognition.
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PMID:Comparative studies of psychological function in patients with advanced cancer. II. Interviewer-rated current and past psychological symptoms. 725 36

A graft-versus-leukemia (GVL) effect has been considered a major factor responsible for cures in patients with hematologic malignancies undergoing allogeneic bone marrow transplantation; however, associated graft-versus-host disease (GVHD) results in significant morbidity and mortality. T-cell depletion reduces the incidence and severity of GVHD but eliminates, at least partially, the GVL effect. Reinfusion of donor T lymphocytes at relapse posttransplantation can induce a potent antitumor response, but GVHD still occurs in the majority of patients. Prior transduction of T lymphocytes with the suicide gene, the viral thymidine kinase (TK), permits specific cell kill on administration of ganciclovir (GCV). Therefore, infusion of TK-transduced T lymphocytes may induce GVL effect and allow for their subsequent selective elimination in case GVHD develops. To evaluate the efficacy and feasibility of this promising approach, anti-CD3-stimulated primary human lymphocytes cultured in interleukin-2 were TK-transduced by a retroviral vector carrying both TK and neomycin-resistance genes. After selection in G418, more than 90% of the cells contained the TK gene as shown by a semiquantitative polymerase chain reaction. In addition, 1 to 5 days of GCV exposure, at clinically achievable concentrations of 20 to 50 micromol/L, induced > or = 90% killing of G418-selected cells without affecting nontransduced cells. Correlation of the extent of T-cell kill and the proportion of TK-gene-transduced cells is consistent with the absence of a bystander effect. Transduced cells were CD3+ and either CD8+ or CD4+ and retained functional properties of untransduced cells. In vivo administration of GCV prevented tumor development after subcutaneous injection of TK-transduced murine myeloma cells (MOPC-11), whereas such an effect was not observed on injection of untransduced cells into the opposite flank. Our studies provide critical information that (1) adequate numbers of TK-transduced lymphocytes can be selected efficiently with > or = 90% purity, (2) selected cells remain functional, (3) 24 hours of exposure to GCV at clinically achievable concentration effects > or = 90% killing of selected cells, and (4) GCV is effective in vivo in killing TK-transduced cells. Based on these data, a clinical study has been initiated in patients with multiple myeloma with persistent or relapsing disease after T-cell-depleted allogeneic transplants.
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PMID:Thymidine kinase (TK) gene-transduced human lymphocytes can be highly purified, remain fully functional, and are killed efficiently with ganciclovir. 902 56

The results of donor lymphocyte infusion (DLI) for treatment of relapse after bone marrow transplantation (BMT) are reviewed. Durable complete remission can be achieved at the molecular level for a majority (more than 70%) of patients with CML, when treated at early relapse. Results are less favourable for acute leukemias, although useful responses have been reported. Data are scarce though promising for myelodysplastic syndromes and multiple myeloma. Major treatment-associated toxicities are GVHD and bone marrow aplasia. The latter complication can be predicted by evaluating the level of residual donor-derived hematopoiesis. Modification of infused cells (CD8 negative selection or transduction with a suicide gene), addition of peripheral blood stem cells, and early implementation of escalating doses may counteract the complications and increase the response rate. Response rate is variably influenced by the presence of chronic GVHD after initial BMT, T-cell depleted BMT, underlying disease and stage at relapse, and the level of mixed chimerism. DLI is a direct demonstration of the graft-versus-leukemia effect (GVL). Because GVL after BMT is sometimes the predominant cause of cure, it may be advisable in such situations to redirect the conditioning regimens for BMT towards engraftment and less immediate cytotoxicity.
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PMID:Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation. 968 28


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