Leukemic Tumors Research Articles

Anti-tumor activity of an ICAM-3 antibody (ICM3) Against human leukemic xenograft tumors in nude mice

Intercellular Adhesion Molecule (ICAM)-3 is a hematopoietic specific counter receptor for a subset of beta 2 integrins. Previously, we observed that specific murine monoclonal antibody (mAb) engagement of ICAM-3 led to apoptosis of a bone marrow-derived myeloid cell population and leukemic cell lines Jurkat and U937 in vitro. Here, we test a proapoptotic anti-ICAM-3 mAb for inhibition of leukemic cell tumor growth in vivo using a nude mouse xenograft model. Initially, the humanized mAb, ICM3, was evaluated for the capacity to trigger apoptosis of Jurkat cells in vitro and was found to do so (P=.034 as compared to control antibody-treated cells). Next, nude mice with solid tumors derived from U937 cells received either ICM3 (n=45) or placebo (n=43) on day 0, 3 and 5. Tumor size was monitored over a 7-day period after which animals were sacrificed and tumors weighed, measured and examined by histology. ICM3 treatment resulted in significantly smaller U937 tumor volumes on days 4, 5, and 6 relative to placebo treatment (p=.016, .012, and .012, respectively). Median volume (interquartile range) of tumors excised on day 7 was 283 (151–451) mm3 for the placebo-treated group versus 137 (60–385) mm3 for the ICM3-treated group (p=.010). Histologic analysis revealed evidence of co-localization of ICM3 with antigen-bearing cells at the site of tumor formation. Taken together, these data document that treatment of leukemic tumors with ICM3 results in reduced tumor growth in vivo.

Involvement of the Larynx by Hemopoietic Neoplasms: An Investigation of Autopsy Cases and Review of the Literature

Involvement of the larynx by hemopoietic tumors is generally considered a rare event and little is known about the associated clinicopathologic features. Laryngeal tissue removed at autopsy from 14 patients with known disseminated hematologic malignancies and at operation from one patient with multicentric malignant lymphoma of low-grade malignancy (MALToma) of the head and neck region was investigated. A systematic survey of the main clinicopathologic features of the published cases of hemopoietic tumors with laryngeal involvement was also performed. Primary involvement of the larynx by hemopoietic neoplasms must be clearly distinguished from secondary involvement by disseminated or leukemic tumors. Most of the primary tumors are localized lesions that may involve the regional lymph nodes (stages IE or IIE). Radiotherapy is the treatment of choice, and the prognosis is generally favorable. However, secondary involvement by disseminated or leukemic disease carries a very poor prognosis in most cases. Extramedullary plasmacytoma and non-Hodgkin's lymphoma (NHL), particularly B-cell lymphoma of high-grade malignancy, appear to be the most common hemopoietic tumors with primary laryngeal involvement, while primary tumors of myelogenous origin (granulocytic sarcoma and mast cell sarcoma) are extremely rare. Extramedullary plasmacytoma and NHL occur mainly in older persons and in men, are generally associated with a relatively short history of hoarseness and dysphagia, and exhibit preferential involvement of the supraglottic parts of the larynx, in particular the epiglottis and aryepiglottic folds. They are generally polypoid, non-ulcerated lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Oligoclonality of moloney leukemias

Induction of leukemia by non-transforming retroviruses results in the appearance of various hematopoietic tumors. It is believed that these tumors are monoclonal. In this work, the clonal nature of Moloney leukemia virus (MoLV)-induced tumors was studied. Two genetic parameters were used in order to identify leukemic clones: the pattern of the proviral integration sites and the rearrangement of the T-cell receptor complex (TCR). In more than 60% of the mice, different leukemic clones populated tumors developed in different organs of the same animal. Genotypic analysis of cell lines derived from a leukemic organ revealed that the tumor is composed of more than one clone. Phenotypic analysis of subclones which were derived from a monoclonal cell line showed variability in the expression of the Thy 1.2 and MHC antigens. The results indicate that MoLV-induced tumors are of oligoclonal nature. Each leukemic organ contains a mixture of leukemic clones, of which one is dominant.

Developmental toxicity of CI-921, an anilinoacridine antitumor agent

CI-921, an anilinoacridine compound active against leukemic and solid tumors, was evaluated for potential developmental toxicity. Intravenous injections of CI-921 in dextrose were given to female Sprague-Dawley rats (0.1, 0.5, and 1.0 mg/kg) on Gestation Days (GD) 6–15 and to female New Zealand White rabbits (0.1, 1.0 and 2.0 mg/kg) on GD 6–18. Appropriate vehicle and untreated controls were included. Maternal and fetal parameters, including external, visceral, and skeletal malformations and variations, were assessed. Treatment of rats with 1.0 mg/kg resulted in maternal toxicity, manifested as reduced body weight gain and food consumption during and after treatment. Reduced fetal body weight, an increased incidence of stunted fetuses, malformations of the axial and appendicular skeleton, microphthalmia, and an increased number of anatomical variations (including anomalies of the axial skeleton and apparent hydronephrosis) also occurred in rats at 1.0 mg/kg. Treatment of rabbits resulted in no apparent maternal toxicity. However, reduced fetal body weight, agenesis of the azygous lobe of the lung, and an increased incidence of variations of the axial skeleton occurred at 2.0 mg/kg in rabbits. These results indicate that CI-921, at the highest dose tested in each species, produced developmental toxicity in the presence of maternal toxicity in rats, but in the absence of maternal toxicity in rabbits.

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MY-1, a fraction extracted from BCG and composed of 70.0% DNA and 28.0% RNA, was examined for its antitumor activity against 9 different syngeneic mouse tumors. Tumor regression was induced in almost all of the mice bearing any of five kinds of solid tumors by repeated intralesional injections of 100 micrograms MY-1. When cells of some tumors were inoculated intradermally together with MY-1, tumor growth was suppressed, lung metastases were inhibited, and the survival times of mice bearing 1 of 3 leukemic tumors were prolonged. Repeated sc injections with MY-1 in sites remote from tumor cell inoculation or repeated iv injections were more or less effective against three kinds of solid tumors. Mice inoculated with Lewis lung carcinoma cells in a hind footpad and whose legs were amputated 9 days later were given iv or sc injections of MY-1 every other day (8 times in total), resulting in substantial prolongation of survival. No direct cytotoxicity of MY-1 for these tumors could be shown in three kinds of experiments, which indicates that the antitumor mechanism of MY-1 is host mediated. MY-1 was equally effective in mice with or without presensitization with BCG, whereas BCG was much more effective in BCG-sensitized mice. This finding suggests that a delayed-type hypersensitivity reaction elicited by BCG protein is not required for the antitumor activity of MY-1.

Common multigenic activation in different human neoplasias.

It was previously shown that a common multigenic component, designated as tumor-specific DNA (tsDNA), was transcriptionally active in human lymphoid neoplasias and only slightly active, if at all, in normal lymphoid cells, including the Priess cell line immortalized by Epstein-Barr virus. In the Burkitt lymphoma-derived Raji cell line, tsDNA corresponded to 2500-3000 distinct transcription units, arbitrarily defined as encoding mRNA chains of 1000 kds each. In the present study, radioactive Raji cell tsDNA was isolated by a recycling procedure which eliminates transcribed DNA sequences common to both the Raji cell and the Priess cell, and was used as a probe for homologous transcripts. The major part of this probe could be hybridized to RNAs from all the human neoplasias studied: cultured cell lines derived from leukemias, malignant lymphomas or sarcomas, leukemic cells or solid tumors (sarcomas and carcinomas) recovered from patients. In contrast, only a minor portion of Raji cell tsDNA could be hybridized to RNAs from non-malignant cells, normal human lymphoid cells or fibroblasts grown in culture, fetal and chorioplacental tissues. It is concluded that a common multigenic set is activated in a wide variety of, and perhaps in all, human neoplasias.

Prognostic features at diagnosis of chronic myelocytic leukemia.

Clinical and laboratory findings at the time of diagnosis were correlated with the survival of 242 patients with chronic myelocytic leukemia. Twelve patients with the blastic stage of the disease (blasts greater than or equal to 29%) had a median survival of eight months. Of the nonblastic patients, 28 without the Philadelphia chromosome had a relatively constant mortality averaging 43% per year and a median survival of 13 months, markedly worse than the Ph1-positive group (mortality, 6% in the first year, 17% in the second year, and the 25% per year, with a median survival of 43 months; P less than 0.001). In the latter group of 202 patients, features reflecting the "quantity" of leukemia (leukocyte count, marrow cellularity, and M:E serum B12, different degrees of splenomegaly, presence or absence of symptoms) had weaker or short-term correlations with mortality, while "qualitative" abnormalities (e.g., increased percentage of circulating blast, extramedullary leukemic tumors, major abnormalities of erythropoiesis or platelet production, marked basophilia or eosinophilia) had strong and persistent correlations with mortality. Chromosome abnormalities in addition to the Ph appeared to have a delayed though significant effect on survival. Serum alkaline phosphatase and SGOT levels did not correlate significantly with survival, but major elevations of serum LDH were associated with increased mortality throughout the course of the disease.

Conformation of free and of integrated Moloney leukemia virus proviral DNA in preleukemic and leukemic BALB/Mo mice

Restriction enzyme analysis has been used to characterize the structure of Moloney leukemia virus (M-MuLV) DNA in preleukemic and leukemic BALB/Mo mice. Leukemogenesis in these mice is accompanied by a somatic amplification of M-MuLV-specific DNA sequences which are derived from the germ line-transmitted Moloney leukemia virus genome. Quantitation by DNA-DNA annealing in solution has shown that this increase of M-MuLV-specific DNA sequences occurs in two steps, a first step from 1 to approximately 2 copies in spleen and thymus of preleukemic mice and a second increase to 3–4 copies following leukemic transformation. Using a specific cDNA probe for restriction enzyme analysis, no somatically acquired M-MuLV copies are detectable in tissues of preleukemic BALB/Mo mice. This indicates that virus integrated at many different chromosomal sites in individual cells. In contrast, restriction enzyme analysis of DNA from leukemic tissues shows 5–8 integrated copies in addition to the endogenous M-MuLV genome. Identical integration patterns are observed in leukemic tumors arising at different anatomical sites in individual animals. Tumors from different animals, however, have distinct integration patterns and no specific integration site common to all tumors can be identified. These results suggest that in BALB/Mo mice transformed cells originate among a population of preleukemic target cells which is heterogenous with respect to integration sites of newly acquired proviral copies. Selection of one transformed cell clone leads to monoclonal disease. Similar results are obtained with BALB/c mice infected with virus as newborns. Gel analysis indicated that unintegrated forms of M-MuLV viral DNA appear in target tissues of preleukemic BALB/Mo mice. Quantitation by quantitative hybridization in solution showed that up to 0.5 copy per cell can be present in thymic DNA from 1− to 5-month-old mice but not in spleens of the same animals. Small amounts of unintegrated proviral DNA are occasionally detected in thymus, spleen, and bone marrow of animals younger than 4 weeks of age. These results provide the first evidence for occurrence of free proviral DNA in animals and suggest that superinfection of target cells with endogenous virus is involved in the process of leukemic transformation.

Distribution of 18F-5-Fluorouracil in tumor-bearing mice and rats

Extensive distribution studies of 18F-5-fluorouracil ( 18F-5-FU) in control and tumor-bearing mice (seven lines) and rats (eight lines) that have been shown or suspected to be responsive; to 5-FU treatment were investigated with 18F-5-FU. Studies were performed as a function of time, loading dose of 5-FU, and after a pretreatment regimen of 5-FU. Following the parenteral administration of 18F-5-FU to tumor-bearing mice and rats there was slight preferential uptake by some of the tumor types, particularly subcutaneous leukemic tumors and breast adenocarcinomas. The degree of concentration in tumor tissue in comparison with surrounding tissues (blood, muscle) was not such as to consider the radiopharmaceutical suitable for tumor localization. However, sufficient amounts of radioactivity localized in some tu,ors so that it might be possible to determine if a correlation exists between tumor uptake and anti-tumor effect of 5-fluorouracil. Another possible area of use might be in regulating the method of administration of the chemotherapeutic agent.

Attempt to immunize guinea pigs against leukemia by skin scarification with leukemic cell suspensions.

An attempt was made to immunize "strain 2" guinea pigs by superficial skin scarification with small doses of L2C leukemic cell suspensions. Among 203 scarified guinea pigs, 32 developed progressively growing leukemic tumors at the site of skin scarification. In 35 guinea pigs small intradermal tumors that appeared at the site of scarification regressed spontaneously; however, 15 guinea pigs in which the intradermal tumor regressed later developed generalized leukemia. In addition, 13 other animals developed generalized leukemia, without an apparent local tumor formation at the site of scarification. A total of 60 out of 203 scarified guinea pigs (30%) died from leukemia.143 Guinea pigs that survived the scarification were challenged by subcutaneous inoculation of massive doses (0.5 ml each of a 10-fold dilution from a 10% extract) of leukemic cell extracts and only 48 (34%) developed leukemia; 95 guinea pigs (66%) resisted the challenge and remained in good health. In a control experiment, 156 untreated "strain 2" guinea pigs were inoculated subcutaneously (0.5 ml each) with L2C leukemic cell suspensions of 10(-2) or 10(-3) dilution, and all but two (99%) developed generalized leukemia.

Further observations on the inhibitory effect of myxoviruses on a transplantable murine leukemia.

SummaryImmunization of mice with parainfluenza viruses NDV or Sendai increases the oncolytic effect of these viruses when pre-infected leukemic cells are injected into C3H mice. Variations in oncolytic activity between different strains of influenza and parainfluenza viruses were noted, and also between two leukemic tumors induced by the Gross virus. Statolon given before virus-infected cells prevents oncolysis but has no effect when given later. Antiserum to NDV or Sendai (plus complement) shows a cytolytic effect in vitro against leukemic cells infected with these viruses.

Chloroma. Report of a patient with unusual rib lesions.

Chloroma is a manifestation of myelogenous leukemia in which leukemic tumors are colored green. The original description by King (10) in 1853 led to the belief that chloroma represented a separate disease entity. In 1937, however, Kandel (9) reviewed 58 cases reported in the literature and found that the chloroma without exception had been associated with myelogenous leukemia. The green color is attributed to reduced breakdown products of hemoglobin (8). In 1966 Filip and Bednář (3) showed in a series of 24 patients marked erythrophagocytosis by tumor cells. Chloroma occurs mainly in children, with predilection for the long bones, calvarium, and periorbital tissues. Roentgenographic descriptions are few, but periosteal elevation was prominent in the patients reported (1, 12). In the original roentgenographic description Gould and LeWald (5) noted underlying new bone at right angles to the shaft. No reports include roentgenographic reproductions of rib chloromas, although isolated rib lesions have been described (11). The present case report is prompted by an unusual roentgenographic appearance resembling the rachitic rosary, with symmetric involvement of the ribs anteriorly by multiple chloromas. Case Report A 10-month-old Caucasian female was admitted with the diagnosis of acute myelogenous leukemia. The child was normal at birth and well until the age of eight months when mild pallor appeared. Three weeks before admission she became anorectic and febrile with rapid respirations. The white blood cell count was 288,000, and many myelocytic blast forms were present. Hemoglobin was 6.4 g per 100 ml. Examination of bone marrow showed diffusely infiltrating acute promyelocytic cells. Treatment with 6-mercaptopurine had been instituted at another hospital. The patient did not improve, and she was transferred to the University of California Medical Center at San Francisco for further therapy. There was no family history of hematologic disease. A maternal grandmother had died of carcinoma of the uterus. Examination revealed an acutely ill female infant in severe respiratory distress. The conjunctivae were pale and the eyes were moderately proptotic. Shotty anterior and posterior cervical lymph nodes were palpable. Intercostal retractions and occasional rhonchi were noted in the chest; no rib masses could be palpated. The liver and spleen were moderately enlarged. The skin contained numerous ecchymoses. Laboratory Data: White blood cell count was 145,000; platelets, 1,000, hematocrit, 21 mm. Aspiration of bone marrow five days after onset of therapy revealed a pronounced hypocellularity with immature blast cells and erythrophagocytosis. Roentgenograms of the chest showed bilateral bulbous expansion of the anterior ends of the second through seventh ribs with periosteal elevation (Fig. 1). Patchy infiltrates were scattered throughout the lungs. Transverse radiolucent bands were seen in the proximal humeral metaphyses.

A Transmissible Leukemia in Mice with Atypical Cells

The transmissible strain of leukemia (S2) herein described originated in a mouse in which benzpyrene had been injected into the spleen. The predominant (malignant) cells of this strain are not typically lymphoid, myeloid, or monocytic in type, and thus far we have been unable to ascertain their origin. The disease can be transmitted to most mice of Stock S, in which the spontaneous disease originated. It can also be transmitted to unrelated mice which receive massive doses of x-rays before and after inoculation, but not to unirradiated unrelated mice. In unrelated mice irradiated with a single dose prior to inoculation, leukemic tumors develop, but regress completely within approximately two weeks. The transmitting agent brought rapidly to −30° C. and kept at that temperature for thirty minutes fails to produce the disease when inoculated into susceptible mice. However, a leukemic cell suspension exposed to a gradual reduction of the temperature to — 70° C. and maintained at that temperature for thirty-two days still possesses the ability to transmit the disease. Leukemic tissue dried in vacuo in the frozen state, glycerinated tissue, and Berkefeld filtrates of similar tissue fail to transmit the disease. This strain of leukemia is described because of characteristics hitherto not recorded in association with mammalian leukemia.

LEUKEMIA—A SARCOMA: BONE EVIDENCE

The etiology of leukemia is still uncertain. To me it resembles sarcoma in a fluid medium. It acts like a malignant growth clinically. In the two cases I report, the morbid anatomy and histologic pathology indicate it to be of a sarcomatous nature. Not only do the leukemic cells invade soft parts, but the bone likewise gives evidence of destructive action of cells and fluids. Since the original suggestion of Bizzozero, many have thought it might be sarcomatous. Osler1in his Principles and Practice of Medicine writes of Willcock's case, where there were growths on the stomach and gastrosplenic omentum, leukemic infiltration of the liver, the cells being outside the capillaries. He furthermore states, Leukemic tumors may occur in the kidneys and liver. Bizzozero showed these tumor cells to be in active fission. Occasionally the sternum, ribs and flat bones show great irregularity and deformity owing to the definite