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PubMed2002

Generation of cytotoxic T cells against virus-infected human brain macrophages in a murine model of HIV-1 encephalitis.

HIV-1 encephalitis (HIVE) and its associated dementia can occur in up to 20% of infected individuals, usually when productive viral replication in brain mononuclear phagocytes (macrophages and microglia) and depletion of CD4(+) T lymphocytes are most significant. T cells control viral replication through much of HIV-1 disease, but how this occurs remains incompletely understood. With this in mind, we studied HIV-1-specific CTL responses in a nonobese diabetic (NOD)-SCID mouse model of HIVE. HIV-1-infected monocyte-derived macrophages (MDM) were injected into the basal ganglia after syngeneic immune reconstitution by HLA-A*0201-positive human PBL to generate a human PBL-NOD-SCID HIVE mouse. Engrafted T lymphocytes produced HIV-1gag- and HIV-1pol-specific CTL against virus-infected brain MDM within 7 days. This was demonstrated by tetramer staining of human PBL in mouse spleens and by IFN-gamma ELISPOT. CD8, granzyme B, HLA-DR, and CD45R0 Ag-reactive T cells and CD79alpha-positive B cells migrated to and were in contact with human MDM in brain areas where infected macrophages were abundant. The numbers of productively infected MDM were markedly reduced (>85%) during 2 wk of observation. The human PBL-NOD-SCID HIVE mouse provides a new tool for studies of cellular immune responses against HIV-1-infected brain mononuclear phagocytes during natural disease and after vaccination.

AIDS Dementia Complex↗

PubMed2002

Survival of fetal skin grafts is prolonged on the human peripheral blood lymphocyte reconstituted-severe combined immunodeficient mouse/skin allograft model.

BACKGROUND: Fetal tissue is considered to be immune privileged and is under extensive investigation as a source of tissue for transplantation. In this paper, we analyzed the immune properties of human fetal and neonatal skin before and after transplantation to severe combined immunodeficient (SCID) mice. Using a human peripheral blood mononuclear cell reconstituted SCID (huPBMC-SCID) mouse model of allograft rejection, we compared the immune response to transplanted fetal and neonatal skin. METHODS: We analyzed human fetal (55-122 days of gestation) and neonatal skin samples by routine histology and immunohistochemistry for the expression of (MHC class I and II antigens before and after transplantation to SCID mice. After transplantation, we injected the mice with huPBMCs and analyzed the survival of neonatal and fetal skin grafts both visually and microscopically. RESULTS: We detected no class II expression in fetal skin of all gestational ages and only weak class I expression after 89 days compared with abundant class I and II expression in neonatal skin before transplantation. When transplanted to SCID mice, fetal skin grafts differentiated and expressed class I and II, but the levels were lower than neonatal grafts. In mice injected with huPBMCs, rejection of neonatal grafts started on day 5, and by day 9 all grafts were rejected. In contrast, rejection of fetal skin grafts was significantly delayed. Rejection started on day 13 and was complete by day 23 (P<0.00005). Histology sections from the rejected grafts showed marked CD3+ T cell infiltration in the human skin with a sharp demarcation between the human and mouse skin, with no T-cell infiltration in the mouse skin. CD4+ and CD8+ T cells were present in the rejected sites in similar densities. CONCLUSIONS: Our results show that fetal skin differentiates and expresses increased amounts of MHC class I and class II antigens when transplanted to SCID mice. However, these levels are much lower than the levels found in neonatal skin. We demonstrate that the survival of human fetal skin allografts is markedly prolonged compared with that of neonatal skin grafts in the huPBMC-SCID mouse model. Our results support the hypothesis that low levels of MHC antigen expression lead to a delay in the rejection of fetal skin and further demonstrate the utility of the huPBMC-SCID mouse model to investigate the molecular and cellular mechanisms of the immune response to human fetal tissues.

Animals↗

PubMed1995

Species-specific metastasis of human tumor cells in the severe combined immunodeficiency mouse engrafted with human tissue.

We have attempted to model human metastatic disease by implanting human target organs into the immunodeficient C.B-17 scid/scid (severe combined immunodeficiency; SCID) mouse, creating SCID-hu mice. Preferential metastasis to implants of human fetal lung and human fetal bone marrow occurred after i.v. injection of human small cell lung cancer (SCLC) cells into SCID-hu mice; the homologous mouse organs were spared. Clinically more aggressive variant SCLC cells metastasized more efficiently to human fetal lung implants than did cells from classic SCLC. Metastasis of variant SCLC to human fetal bone marrow was enhanced in SCID-hu mice exposed to gamma-irradiation or to interleukin 1 alpha. These data indicate that the SCID-hu mice may provide a model in which to study species- and tissue-specific steps of the human metastatic process.

Animals↗

PubMed2000

Transmission of porcine endogenous retroviruses in severe combined immunodeficient mice xenotransplanted with fetal porcine pancreatic cells.

BACKGROUND: Xenotransplantation using pig organs or tissues may alleviate the human donor organ shortage. However, one concern is the potential transmission of pig pathogens to humans, especially pig endogenous retroviruses (PERV), which infect human cell lines in vitro. In this report, the cross-species in vivo transmission of PERV by xenotransplantation was studied using a severe combined immunodeficient (SCID) mouse model. METHODS: Twenty-one SCID mice were transplanted with fetal pig pancreatic cells and left for periods from three to 41 weeks before being killed. DNA and RNA were extracted from liver, spleen, and brain of these mice, and examined for PERV using nested polymerase chain reaction (PCR) and reverse transcriptase-PCR. The pig mitochondrial cytochrome oxidase II subunit gene (COII) was also amplified to monitor the presence of pig cell microchimerism in xenotransplanted tissues, and a housekeeping gene was included to monitor the DNA quality and quantity. RESULTS: Examination of 39 DNA samples from tissues of the 21 xenografted mice identified two mouse tissues (M4-liver and M19-spleen) that were positive for PERV but negative for COII. A total of 23 (59%) of the mouse tissues were positive for both PERV and COII, 6 (16%) were negative for both, and 8 (20%) were positive for COII only. PCR and direct sequencing of the PCR products identified three PERV variants, which were different from the PERV sequence detected by PCR direct sequencing from the pig donor cells. CONCLUSIONS: The PERV+/COII- results from M4-liver and M19-spleen indicated the presence of PERV transmission from pig to mouse tissue. The PERV variants detected in the mouse tissues indicated that different PERVs were transmissible from the pig to mouse tissue during xenotransplantation. The negative reverse transcriptase-PCR results for PERV from three mouse samples including M4-liver and M19-spleen suggest there was no active PERV transcription in the mouse tissues, although this would need to be studied further.

Animals↗

PubMed1997

HIV-1 pathogenesis and therapeutic intervention in the SCID-hu Thy/Liv mouse: a model for primary HIV-1 infection in the human thymus.

The SCID-hu Thy/Liv mouse is a model for the analysis of human thymopoiesis. It has been constructed by engrafting fragments of human fetal liver and thymus into the immunodeficient C.B-17 scid/scid (SCID) mouse. The resulting 'Thy/Liv' organ promotes long-term differentiation of human T cells. Given the apparently normal physiology of the SCID-hu Thy/Liv organ, it has been used to explore the pathophysiologic mechanisms of HIV-1 infection in vivo, and to test therapeutic modalities such as anti-HIV-1 drugs and haematopoietic stem cell (HSC)-based gene therapy. In this review, I will summarise what we have learned from the SCID-hu Thy/Liv model, with a focus on recent findings in HIV-1 replication and therapy. Unique HIV-1 determinants have been identified which are required for replication in the Thy/Liv organ but not for replication in PBMC or in T cell lines in vitro. The mechanism of HIV-1 induced thymus depletion is not clear. It is correlated with high levels of HIV-1 replication. Both direct and indirect mechanisms may be involved. In addition to preclinical evaluation of anti- HIV-1 drugs, the SCID-hu Thy/Liv mouse has also been successfully used to test the feasibility of HSC-based gene therapy. A number of improved SCID-hu models have been constructed to meet different requirements. Using these SCID-hu Thy/Liv models, current/future efforts will provide insightful information for understanding pathogenesis and designing therapeutic interventions against HIV-1 infection in humans, especially in paediatric patients. Copyright 1997 John Wiley & Sons, Ltd.

Journal Article↗

PubMed1996

Lack of detectable defect in DNA double-strand break repair and DNA-dependent protein kinase activity in radiosensitive human severe combined immunodeficiency fibroblasts.

The initial step of the V(D)J recombination occurs through the generation of a DNA double-strand break (dsb). Defects in the DNA-dependent protein kinase complex (DNA-PK) result in an inability to perform either V(D)J recombination or any dsb repair effectively. The human autosomal T-B-severe combined immunodeficiency (SCID) condition is characterized by an absence of both B and T lymphocytes and is accompanied in some patients by an increase in gamma-ray sensitivity (T-B-RS SCID) comparable to that found in mouse SCID cells. We show here that cells from six patients with T-B-RS SCID had normal DNA-dsb repair kinetics. Furthermore, DNA-PK activity was present in extracts from these human T-B-RS SCID fibroblasts. We therefore conclude that some human T-B-RS SCID disorders are not caused by a defect in an essential DNA-PK component.

B-Lymphocytes↗

PubMed1994

Mature helper T cell requirement for immunoglobulin production by neonatal native B cells injected intraperitoneally into severe combined immunodeficient (SCID) mice.

It is accepted that human neonatal naive B cells produce mainly IgM in vivo as well as in vitro. Our previous work has demonstrated that i.p. injection of neonatal B cells together with adult mature T cells induces substantial levels of human IgG in the serum of SCID recipient mice. The present study was further attempted to determine the cellular components required for immunoglobulin production by neonatal B cells in SCID mice. When neonatal B and adult T cells were transferred into the SCID mice, human immunoglobulins, largely of IgG, were maximally detected in the serum around 6 weeks after a cell transfer. Depletion of CD4+ T cells from adult T cells resulted in undetectable levels of human immunoglobulin in the serum. By contrast, CD4+ T cell-enriched populations exhibited an enhancing effect on immunoglobulin production by neonatal B cells. Higher levels of immunoglobulin, including IgA and IgM, were detected in the peritoneal fluid than in the serum as early as 2 weeks after the cell transfer. Human T cells expressing activation antigens such as CD45RO and HLA-DR antigens were identified in the peritoneal lavages. These results suggest that neonatal naive B cells are able to differentiate into cells producing all classes of immunoglobulin in the presence of mature CD4+ T cells in a SCID mouse environment. The peritoneal cavity of SCID mice appears to provide a suitable place for immune responses by human cells, possibly in association with a certain xenogeneic reaction.

Adult↗

PubMed1993

Molecular analysis of neurovirulent strains of Sindbis virus that evolve during persistent infection of scid mice.

To understand the role of tissue-specific adaptation and antibody-induced selectional pressures in the evolution of neurovirulent viruses, we analyzed three strains of Sindbis virus isolated from the brains of persistently infected scid mice and four strains of Sindbis virus isolated from the brains of scid mice with viral reactivation following immune serum treatment. For each viral isolate, we tested neurovirulence in weanling BALB/c mice and sequenced regions of the E2 and E1 envelope glycoprotein genes that are known to contain important determinants of Sindbis virus neurovirulence. One strain isolated from a persistently infected scid mouse and two strains isolated from scid mice with viral reactivation were neurovirulent, resulting in mortality in 80 to 100% of weanling BALB/c mice. All three neurovirulent strains contained an A-->U change at nucleotide 8795, which predicts a Gln-->His substitution at E2 amino acid position 55. No nucleotide changes were detected in the other sequenced regions of the E2 and E1 envelope glycoprotein genes or in the avirulent isolates. Our findings indicate that tissue-specific adaptations, rather than antibody-induced selectional pressures, are a critical determinant of the evolution of neurovirulent strains of Sindbis virus and provide evidence that E2 His-55 is an important neuroadaptive mutation that confers neurovirulence properties on Sindbis virus.

Alphavirus Infections↗

PubMed1992

Control of human B cell tumor growth in severe combined immunodeficiency mice by monoclonal anti-B cell antibodies.

Severe combined immunodeficiency (scid) mice develop EBV (+)B cell tumors after infusion of EBV(+)B cells or of B cells and EBV. In this study, scid mice were infused with B cell lines derived from three patients who developed a B lymphocyte proliferative disorder after bone marrow or organ transplantation. Intraperitoneal injection of 5 x 10(6) B cells induced tumor growth in all mice, leading to death within 60 d. Human B cells were identified in spleen and bone marrow by means of immunofluorescence or EBV genome amplification, and human IgM was detected in serum. Infusion of murine monoclonal antibodies specific for human B cell membrane antigens CD21, CD24, and CD23 was effective in 80% of animals, against two of the three cell lines preventing tumor development or inducing remission according to the time of treatment. The effect was antibody dose dependent and was optimal with four intravenous infusions of at least 0.1 mg 4 d apart. Human IgM in serum and human B cells in spleen and bone marrow became undetectable when peritoneal tumors regressed completely. Infusions of IgG1 isotype-matched anti-CD4 antibody or anti-CD3 antibody had no effect. Tumors developed or recurred in 50% of these animals injected with one of the B cell line 3 mo after treatment was stopped. The same anti-CD21 and anti-CD24 antibodies had been used to treat the three patients, and shown similar degrees of effectiveness as in the scid mouse model. These results indicate that scid mice may be suitable for assessing therapeutic approaches to human B cell proliferation.

Animals↗

PubMed1995

In vivo sequestration of Plasmodium falciparum-infected human erythrocytes: a severe combined immunodeficiency mouse model for cerebral malaria.

Cerebral malaria is a fatal complication of infection by Plasmodium falciparum in man. The neurological symptoms that characterize this form of malarial disease are accompanied by the adhesion of infected erythrocytes to the vasculature of the brain. To study this phenomenon in vivo, an acute phase severe combined immunodeficiency (SCID) mouse model was developed in which sequestration of P. falciparum-infected human erythrocytes took place. During acute cerebral malaria in humans, the expression of intercellular adhesion molecule-1 (ICAM-1) is induced in vascular endothelium by inflammatory reactions. Acute phase ICAM-1 expression can also be obtained in SCID mice. The endothelium of the midbrain region was the most responsive to such inflammatory stimulus. It is noteworthy that the reticular formation in the midbrain controls the level of consciousness, and loss of consciousness is a symptom of cerebral malaria. We found that infected human erythrocytes were retained 24 times more than normal erythrocytes in ICAM-1-positive mouse brain. Sequestration to the brain was reduced by anti-ICAM-1 antibodies. These in vivo results were confirmed by the binding of P. falciparum-infected erythrocytes to the ICAM-1-positive endothelium in tissue sections of mouse brain. We conclude that the SCID mouse serves as a versatile in vivo model that allows the study of P. falciparum-infected erythrocyte adhesion as it occurs in human cerebral malaria. Upregulation of ICAM-1 expression in the region of the midbrain correlates with increased retention of malaria-infected erythrocytes and with the symptoms of cerebral malaria.

Animals↗

PubMed1996

Growth and immunogenicity of human glioma in severe combined immunodeficiency-human mice.

The severe combined immunodeficiency (SCID) mouse was investigated as a model system to study the growth and immunogenicity of human gliomas. Human glioma cell lines U-251MG, KNS-42, SF-188, A-172, and T-98G were injected subcutaneously into SCID mice. The cell lines U-251MG and KNS-42 grew as large, subcutaneous masses; SF-188, A-172, and T-98G did not grow. Glioma-immune system interactions were studied by the transplantation of human peripheral blood lymphocytes into tumor-bearing SCID mice. In the resultant SCID-human (SCID-hu) mice, transplanted lymphocytes infiltrated into the subcutaneously growing tumors and expressed the surface markers of human B, T, and natural killer cells. The SCID-hu mouse is a potentially powerful model to study the basic tumor biology of some human gliomas and also represents a useful screening system to evaluate experimental immunotherapies for brain tumors.

Animals↗

PubMed2001

Expression of angiogenic factors in juvenile rheumatoid arthritis: correlation with revascularization of human synovium engrafted into SCID mice.

OBJECTIVE: Although increased vascularity was noted in early histopathologic studies of juvenile rheumatoid arthritis (JRA) synovium, the available data on angiogenesis in JRA are very limited. The main purposes of this study were to assess expression of the key angiogenic factors in JRA synovium, and to evaluate a SCID mouse model of JRA as an approach to study in vivo regulation of the expression of these factors in JRA. METHODS: RNase protection assay was used to assess the expression of the key angiogenic factors in fresh JRA synovium and in JRA synovial tissue fragments that had been minced and then implanted into SCID mice. Vascularity of the samples was assessed by immunohistochemical staining for von Willebrand factor. Synovial specimens obtained from patients with osteoarthritis (OA) or other noninflammatory arthropathies were used as controls. RESULTS: Detectable levels of messenger RNA for vascular endothelial growth factor and angiopoietin 1 and their respective receptors, as well as endoglin and thrombin receptors, were present in all JRA tissue specimens studied. The levels of expression of these factors in JRA tissues were significantly higher than those in tissues obtained from patients with OA or other noninflammatory arthropathies. Furthermore, increased expression of the key angiogenic factors in the fresh JRA tissues correlated with the exuberant revascularization of JRA minced tissue fragments implanted into SCID mice. This was in sharp contrast to the poor revascularization of implanted OA tissues. CONCLUSION: JRA synovium is characterized by high angiogenic activity. SCID mouse-human JRA synovium chimeras may provide a good approach to study the in vivo regulation of angiogenesis in JRA.

Angiopoietin-1↗

PubMed1994

Variability of a bacterial surface protein and disease expression in a possible mouse model of systemic Lyme borreliosis.

During persistent infection of scid mice with Borrelia turicatae, an agent of relapsing fever and neuroborreliosis, there was variation in the surface proteins the bacteria expressed and in disease manifestations over time. Two serotypes, A and B, were isolated from the mice, cloned by limiting dilution, and further characterized. The only discernible difference between the two variants was in the size of the major surface protein they expressed: serotype A had a variable major protein (Vmp) of 23,000, and serotype B had a Vmp of 20,000. When other scid mice were inoculated with clonal populations of A and B, the infections were similar with respect to onset and degree of spirochetemia, involvement of the eye and heart, and occurrence of a peripheral vestibular disorder. However, there were differences between the serotypes in other respects: (a) serotype B but not A caused reddened and significantly enlarged joints, markedly impaired performance on a walking bar, and severe arthritis by histologic examination; (b) serotype A but not B invaded the central nervous system during early infection; and (c) serotype A penetrated monolayers of human umbilical vein endothelial cells more readily than did serotype B. The combination of arthritis, myocarditis, and neurologic disease resembled human Lyme borreliosis. The findings indicate that differences in disease expression are determined by variable surface proteins of the bacterium and that scid mouse infections with B. turicatae provide a model for the study of the pathogenesis of Lyme borreliosis and other persistent spirochetal diseases.

Animals↗

PubMed1998

Granulocytic ehrlichiosis in the laboratory mouse.

C3H mice that were inoculated with ehrlichiae isolated from a patient with human granulocytic ehrlichiosis (HGE) developed anemia and leukopenia, but by day 24, they returned to normal values. Granulocytic morulae were present in peripheral blood and spleen smears on days 5 and 10, and there was a reduction in morulae on day 17. Ehrlichiae were present in HL-60 cell cultures of blood and spleen from all mice at all intervals. Pathogenicity, but not infectivity, waned with mouse passage but could be resurrected by SCID mouse passage. Various methods were tested for their relative sensitivity in detecting infection: blood smears, HL-60 cell cultures, polymerase chain reaction (PCR) amplification of a 16S recombinant DNA target, and a mouse infectivity assay. All assays detected the HGE agent in blood during early infection, but PCR and the mouse infectivity assay were most sensitive during late infection. Xenodiagnosis demonstrated that mice remain persistently infected through 55 days.

Age Factors↗

PubMed2006

Sensitized CD8+ T cells fail to control organism burden but accelerate the onset of lung injury during Pneumocystis carinii pneumonia.

While CD8+ cells have been shown to contribute to lung injury during Pneumocystis carinii pneumonia (PCP), there are conflicting reports concerning the ability of CD8+ cells to kill P. carinii. To address these two issues, we studied the effect of the presence of CD8+ cells in two mouse models of PCP. In the reconstituted SCID mouse model, depletion of CD8+ cells in addition to CD4+ cells after reconstitution did not result in increased numbers of P. carinii cysts compared to the numbers of cysts in mice with only CD4+ cells depleted. This result was observed regardless of whether the mice were reconstituted with naïve or P. carinii-sensitized lymphocytes. In contrast, reconstitution with sensitized lymphocytes resulted in more rapid onset of lung injury that was dependent on the presence of CD8+ cells. The course of organism replication over a 6-week period was also examined in the CD4+-T-cell-depleted and CD4+- and CD8+-T-cell-depleted mouse model of PCP. Again, the organism burdens were identical at all times regardless of whether CD8+ cells were present. Thus, in the absence of CD4+ T cells, CD8+ T cells are a key contributor to the inflammatory lung injury associated with PCP. However, we were unable to demonstrate an in vivo effect of these cells on the course of P. carinii infection.

Animals↗

PubMed1993

Infection of immunodeficient mice with a mouse-adapted substrain of the gray strain of Babesia microti.

A mouse-adapted substrain was recovered from a severe combined immunodeficient (SCID) mouse inoculated with the Gray strain of Babesia microti. In contrast to the original Gray strain, infection with this substrain (Gray/mo strain) resulted in a high level of parasitemia for a long period in SCID and nude mice, whereas immunocompetent BALB/c mice controlled the infection. The infection profile with the Gray/mo strain was closer to that of human babesiosis than that with the original Gray strain, suggesting usefulness of this mouse model for immunological studies of babesial infection. No antibody activity was revealed in sera of the infected SCID and nude mice. Although strong antibody activity was shown in the sera of the recovered BALB/c mice, no protective activity was demonstrated by the immune serum. Adaptive transfer of thymocytes from the normal BALB/c mouse resulted in SCID and nude mice being able to control the infection, indicating that cell-mediated immunity played a major role in control of infection with B. microti. However, because the reconstituted mice also produced significant antibody titer, antibody remains a possibility for a supportive role in control of the infection.

Animals↗

PubMed2001

Evaluation of recombinant interleukin-2 immunotherapy for human hemangiosarcoma in a SCID mice model (WB-SCID).

We treated the patients with cutaneous hemangiosarcoma with recombinant interleukin-2 (rIL-2) immunotherapy that showed clear therapeutic effects. This immunotherapy is popular for the treatment of hemangiosarcoma in Japan. The purpose of this study is to clarify the clinical effects in an animal experiment. After establishing a SCID mouse model of human hemangiosarcoma WB-SCID, we used this model to investigate anti-tumor effects of rIL-2 and LAK cells. We demonstrated that hemangiosarcoma cells are LAK-sensitive, and LAK cells induced by rIL-2 suppress the growth of hemangiosarcoma. Our results may assure the clinical effects of rIL-2 immunotherapy on hemangiosarcoma.

Aged↗

PubMed2000

The topoisomerase I inhibitor DX-8951f is active in a severe combined immunodeficient mouse model of human acute myelogenous leukemia.

The severe combined immunodeficient (SCID) mouse model of human acute myelogenous leukemia (AML) is a unique system for preclinical in vivo evaluation of the activity and toxicity of new agents. The topoisomerase I (topo I) inhibitor topotecan is active in patients with AML and myelodysplastic syndromes. DX-8951f is a novel topo I inhibitor with more potent antitumor effects than topotecan or CPT-11 in vitro. To study the in vivo activity of DX-8951f, 6-week-old female SCID mice received injections into the tail vein with 2 x 10(7) exponentially growing KBM-3 cells. In each experiment, three to five sets of five mice were treated with DX-8951f doses ranging from 7.5 to 80 mg/kg and at schedules of 1, 3, and 5 days; a control set of five mice was treated with the drug vehicle alone. One group received DX-8951f on day 7 of the inoculation with KBM-3 (early-treatment group). To study the activity of DX-8951f in advanced disease, a second group was treated 1 month after the inoculation, when the animals were developing symptoms (late-treatment group). The study end point was the duration of survival until death from leukemia, which was assessed clinically and by the presence of the human DQ alpha gene in tissue samples by PCR. Six experiments were conducted with 170 animals. Survival was higher in both the early- and late-treatment groups than in untreated controls, and the treated groups had significantly less central nervous system disease. Significantly improved survival was observed in animals treated early with 60 and 80 mg/kg as a single injection, with 15 and 20 mg/kg over 3 days, and with 7.5 and 10 mg/kg over 5 days. In the late-disease model (treatment starting on days 28-35), improved survival was observed with a single dose of 80 or 20 mg/kg over 5 days. Dose escalation was limited by dilution problems at the 1-day schedule and by toxicity (mainly gastrointestinal) of the prolonged schedules. Both efficacy and toxicity were dose schedule dependent, increasing with higher doses and prolonged exposure. By establishing the antileukemic activity of DX-8951f against human AML transplanted into SCID mice at doses below the LD10, our data provide a rationale for clinical evaluation of the drug in patients with AML and favor the use of prolonged administration.

Animals↗