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Treatment of gamma radiation-induced transplanted leukemia in ICRC mice by liposomally encapsulated 5-fluoro uracil.

The present investigation reports on the efficacy of 5-FU encapsulated in liposomes for the treatment of leukemia using a murine model of gamma radiation-induced transplantable leukemia in ICRC strain of mice. Multi-lamellar vesicles (MLVs) or large unilamellar vesicles (REVs) prepared using phosphatidyl choline and cholesterol in a molar ratio of 8:2 for neutral and 7:2:1 for charged vesicles were administered as a single i.p. dose in mice. 5-FU encapsulated in MLVs at a concentration of 0.6-2.5 mg/kg had no effect, whereas REVs at a single i.p. dose of 9 mg/kg increased survival of leukemic mice with T/C = 138%, decreased peripheral blood count and considerably reduced infiltration of leukemic cells in different tissues (supported by histopathology) as compared to 60 mg/kg of free drug (LD10 = 70 mg/kg).

Animals↗

Survival in the elderly with acute leukemia.

The natural history of acute leukemia in the elderly is not well understood. There is disagreement about the value of treatment other than by supportive measures. In this study, the survival predictive power of 9 variables was analyzed in 103 patients aged 70 or older for whom a bone-marrow cytologic diagnosis of acute leukemia had been made at a referral hospital during the 30-year period, 1947--1976. When given, treatment was uniformly conservative. Blood leukocyte and platelet counts and hematocrit values at the time of diagnosis, sex, treatment, and the calendar year of diagnosis were significant (P less than 0.01) predictors of survival duration. Initial hematologic measurements, presumably reflecting the degree of leukemic cell infiltration of the bone marrow, were the strongest predictors of survival, whereas leukemic cell type had no predictive power. Survival increased significantly (P less than 0.01) during the 30-year period of the study, possibly more attributable to improved supportive care than to specific antileukemic therapy. Apparently survival is at least partly determined at the time of diagnosis, and conservative therapy often may be beneficial rather than detrimental.

Acute Disease↗

Unusual skin and testicular lesions in a patient with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal disorder of hematopoetic stem cells with myelodysplastic and myeloproliferative features. Skin infiltration by leukemic cells is rare in CMML. A case is presented with severe dermatological involvement and concomitant testicular infiltration. An unusual feature was the evidence that the skin was the primary site of an acute leukemic transformation.

Journal Article↗

Cell adhesion molecules in HTLV-I infection.

Cell adhesion molecules expressed on the cell surface of leukemic cells and on vascular endothelial cells may play a key role in trafficking, localization, and infiltration of leukemic cells in adult T-cell leukemia (ATL). The predominant adhesion pathway between ATL cells or human T-cell leukemia virus type I (HTLV-I)-infected cell lines and human umbilical vein endothelial cells (HUVECs) is an E-selectin-mediated pathway as determined by studies using adhesion-blocking monoclonal antibodies, although fresh leukemic cells and HTLV-I-infected cell lines also expressed LFA-I, VLA-4, L-selectin, and CD44. Our study also strongly suggested the presence of adhesion pathway(s) mediated by as yet unknown cell adhesion molecule(s), to which we have recently developed monoclonal antibodies.

Cell Adhesion↗

[Establishment and biological characterization of a transplantable BALB/c mouse erythroblastic leukemia model].

OBJECTIVE: Biological characterization of a BALB/c mouse transplantable erythroblastic leukemia model EL9611. METHODS AND RESULTS: The original erythroblastic leukemia (EL) mouse was obtained by 7,12-DMBA induction. The spleen cell suspension from the original EL mouse was injected into the same inbred BALB/c strain mice. After successive transplantation for 20 generations, the incidence of EL was 100% without spontaneous remission. There was a linear relationship between the survival time of the EL mice and the number of leukemic cells inoculated. When 10(6) leukemic cells were inoculated intravenously, the EL mice survived 10.2 +/- 1.3 days. Invasion of leukemic cells involved mainly in the bone marrow, the spleen and the liver. There was no obvious infiltration of leukemic cells in lymph-nodes and thymus. In peripheral blood, there were a large number of leukemic cells and most of them were basophilic or polychromatophilic erythroblasts. At the advanced stage, the mice developed anemia and thrombocytopenia. The reaction of the leukemic cells for hemoglobin staining was positive or weakly positive. While the peroxydase reaction was negative, Thy-1 antigen and Fc-recepter were not presented. No virus-like particles was found in the cells under electron microscope. EL9611 leukemia model was sensitive to some antitumor drugs used in clinical therapy. CONCLUSION: The establishment of EL9611 leukemia model offered a useful tool for studying proliferation and differentiation of erythroid cells, as well as pathogenesis and experimental treatment of non-virus erythroid malignancy.

9,10-Dimethyl-1,2-benzanthracene↗

Induction of interdigitating reticulum cell-like differentiation in human monocytic leukemia cells by conditioned medium from IL-2-stimulated helper T-cells.

Monocytic leukemia (MoL) cells were obtained from the peripheral blood of a patient in whom the leukemic cells infiltrating various lymphoreticular organs exhibited features intermediate between interdigitating reticulum cells (IDC) and ordinary phagocytic macrophages, whereas the leukemic cells in the peripheral blood were essentially monocytic and lacked such features. Peripheral blood CD4+ T-cells were established as an interleukin-2-dependent T-cell line. When the MoL cells were exposed for a few days to conditioned medium from the T-cell line, they extended several dendritic cytoplasmic projections and became intensely positive for HLA-DR antigen, cytoplasmic S-100 beta protein, and CD1 antigen. Functionally, the conditioned medium significantly down-regulated Fc-mediated and Fc-independent phagocytic activities, and the levels of lysosomal enzymes such as lysozyme and nonspecific esterase in the MoL cells. Moreover, the conditioned medium significantly up-regulated the accessory cell function of the MoL cells as measured by the primary allogenic mixed leukocyte reaction (MLR). Furthermore, the conditioned medium significantly down-regulated the expression of CD14 antigen. Biochemical analysis indicated that the factor responsible for these changes is a protein which is distinct from known human cytokines and whose molecular weight is approximately 31 kDa. These findings suggest that IDC are closely related the monocytic lineage and that helper T-cells play an important role in constructing the microenvironment of T-lymphoid tissues which is necessary for the differentiation and maturation of IDC.

Adult↗

Effects of leukemic cells on hematopoiesis in radiation-induced murine erythroleukemia.

Erythroleukemia occurred in a BCF1 mouse after X-irradiation. This leukemia was maintained by leukemic cell transplantation successively without changes in the characters of leukemia. According to leukemic cell proliferation, peripheral blood leukemic cells increased in number, and anemia and granulocytopenia developed. Following leukemic cell infiltration, granuloid-committed stem cells (CFU-C) in bone marrow decreased but those in spleen increased. Neither leukemic cells nor leukemic cell-conditioned medium inhibited CFU-C culture in vitro. Effects of leukemic cells on hematopoiesis were discussed.

Animals↗

[Intracerebral myeloblastoma developed in a patient with acute monocytic leukemia associated with inv (16) (p13q22)].

A 26 year-old man was diagnosed as having acute monocytic leukemia (M5b: FAB classification) associated with inv (16) (p13q22). Remission induction therapy showed good results, but two years later, he complained visual blurring and revealed right papilledema. Lumbar puncture showed leukemic cell infiltration. Irradiation to the orbita, intrathecal injection of MTX and Ara-C, until the cerebrospinal fluid cleared of leukemic cells, and chemotherapy were performed. One month later, he also complained visual blurring and left papilledema was found. After whole brain irradiation, intrathecal injection and chemotherapy, papilledema disappeared. Then, one year later, paralysis of right lower extremity appeared and brain computed tomography (CT) demonstrated tumor with increased density in the left frontal lobe, which enhanced with contrast material. Analysis of spinal fluid demonstrated abnormal cells. He was treated radiation therapy combined with intrathecal MTX and Ara-C. The patient survives currently three years after diagnosis and remains free of central nervous system disease. Because the patients with inv (16) have a high incidence of CNS involvement, they should be monitored closely with periodic lumber punctures.

Adult↗

[Morphogenesis of neuroleukemia].

A comparative study of neuroleukemia in children with acute leukemia and in mice with experimental leukemia was carried out. Spontaneous leukemia in AKR mice and transplantation leukemia (LIO-I, La, P388, L-5178Y) were shown to be adequate models for investigations on the pathogenesis of neuroleukemia. The initial morphological manifestations of neuroleukemia consisted in infiltration of dura mater of the brain and epidural space, particularly of the lumbar region of the spine. The leukemic cell infiltrates originating from the bone marrow spread along the walls of vascular anastomoses between the venous system of the skull and vertebrae on the one hand, and dura mater of the brain and epidural space of the spinal cord, on the other.

Acute Disease↗

[Primary myelofibrosis with severe bone pain].

An 80-year-old man was admitted with bone pain, affecting both lower limbs and the dorsa of the feet, in September, 1991. Primary myelofibrosis was diagnosed. Bilateral x-ray films of the tibia, fibula, femur and vertebra revealed osteoporosis, but this was considered an unlikely source of the bone pain. The bone pain subsequently disappeared, but then became severe in both lower limbs and the dorsa of the feet and was accompanied by leukemic transformations in February, 1992. He died of aspiration pneumonia in July, 1992. Autopsy revealed microfractures with osteoporosis and infiltration of leukemic cells in the periosteum of the left tibia, which may have caused the bone pain. This case provides useful information to analyze the cause of bone pain in patients with myelofibrosis.

Aged↗

Leukemic cell membrane from acute myelogenous leukemias with massive mast cell infiltration has a mast cell differentiation activity under culture condition containing interleukin 3.

Five cases of acute myelogenous leukemia with massive mast cell infiltration in bone marrow and leukemic tumors of the soft tissue were examined to elucidate the relationship between leukemic cells and mast cells. Leukemic cells in each case showed no basophil/mast cell features and differentiated to neutrophil-like cells in liquid culture. Isolated mast cells failed to proliferate with or without growth factors used irrespective of culture conditions. Mononuclear cell fraction obtained from all patients gave rise to relatively numerous mast cells in interphase culture using IL-3 but not in other culture systems. The simultaneous addition of leukemic cell membrane and IL-3 or delayed addition of leukemic cell membrane produced more numerous and mature mast cells in the upper layer of interphase culture using IL-3. However, addition of leukemic cell membrane alone failed to increase the number of mast cells. Similar results were obtain using mononuclear cells obtained from volunteers and cord blood cells. These results indicate that a cell to cell contact or interstitial substance together with IL-3 are essential requirements for growth and maturation of mast cell precursors and that the cell membrane itself in some cases of leukemia has the ability to induce maturation of mast cell precursors.

Adolescent↗

[All-trans retinoic acid was effective for marked skin infiltration in a relapsed acute myelogenous leukemia (AML-M2) patient with t(12; 17)].

A 64-year-old man who had taken acute myelogenous leukemia (AML-M2) in 1989 have relapsed with t(12; 17) (p13; q11.2-21) chromosomal abnormality and presenting marked infiltration to the skin in 1994. Blasts were seen on his peripheral blood smear (15%) and bone marrow examination showed increased leukemic cells (56%), with maturation. Leukemic cells expressed CD13 and CD33 antigen but not HLA-DR. Although leukemic cells had not promyelocytic feature morphologically, detection of PML/RAR alpha infusion signal of peripheral leukemic cells were positive for 8% (1% for control) by fluorescence in situ hybridization method. Because he did not response to standard combination chemotherapy and because we considered the possibility that t(12; 17) (p13; q11.2-21) observed in this case are t(15; 17) variant, we tried all trans retinoic acid (ATRA) to him. Interestingly, ATRA was very effective for skin lesion but hematologically it had no effect at all, and he died because of bacterial pneumonia.

Antineoplastic Agents↗

Acute leukemia presenting as diabetes insipidus and bilateral exudative retinal detachment--a case report.

To report an unusual case of leukemia presenting as both bilateral exudative retinal detachment (ERD) and central diabetes insipidus (DI), we evaluate the clinical hematological records including bone marrow aspirations and CSF tapping, both osmolarity and electrolytes concentration of the serum and urine, brain MRI, fundus photographs and fluorescein angiographs in this 25-year-old female patient. Examinations of peripheral blood and bone marrow aspiration confirmed the diagnosis of acute myelogenous leukemia (AML-M0). Fluorescein angiography (FA) revealed bilateral ERD, dense choroidal leukemia cell infiltration with overlying retinal pigment epithelium (RPE) dysfunction and focal areas of choroidal infarction. Changes in both osmolarity and electrolytes concentration of the serum and urine from vasopressin test supported the diagnosis of central DI. Central DI and ERD may be presenting signs of acute leukemia and both may represent CNS involvement. In our case, dense choroidal leukemic cell infiltration results in devitalization of RPE and choroidal infarction. Leukemic disruption of hypothalamic pituitary area may lead to complete or partial deficiency of antidiuretic hormone (ADH). Rapid improvement in visual acuity and partial symptom relief of DI may ensue from appropriate chemotherapy and nasal DDAVP (1-desamino-8-D-arginine vasopressin) supply.

Adult↗

HB-1, an acute myeloid leukemic cell line with the capability of infiltrating into the brain in CBA/N mice.

An acute myeloid leukemic HB-1 cell line was cloned and established from the spleen cells of irradiated CBA/N mice. Acute myeloma leukemia-like syndrome would be induced in normal CBA/N mice after intravenous injection of HB-1 cells, and the death of mouse happened within about two weeks. In general, leukemic cells transplanted into the mice would infiltrate into the hematopoietic organs, lungs, kidneys and liver. An interesting observation in our study was that HB-1 cells were present not only in the lung, kidney, and liver but also in the cerebrum and cerebellum. It was beyond our expectation that the leukemic cells could go through the blood-brain barrier in most circumstances. On the basis of the observation, we expect that HB-1 cells could be used as a very useful model to elucidate the mechanism of infiltrating the blood-brain barrier for certain type of cells.

Animals↗