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Biomedical subjects

I R Hart

Publications and source records attributed to I R Hart.

At least 145 records · Page 8Linked to original sources
PubMed1984

Inhibited growth of a reticulum cell sarcoma (M5076) induced in vitro and in vivo by macrophage-activating agents.

The tumor M5076 is highly malignant in vivo; however, in vitro M5076 tumor cells express many of the differentiated characteristics of an activated macrophage. Recently, we reported that this macrophage tumor (M5076) can be induced to cease cellular division following in vitro exposure to macrophage-activating agents, which we felt was due to the induction of terminal differentiation. In the present study, we report that not all macrophage-activating agents halt the proliferation of M5076 tumor cells in vitro, and we present evidence that the treatment of mice bearing M5076 tumor cells with lipopolysaccharide is a highly effective therapeutic modality. Therapy protocols using multiple injections of lipopolysaccharide are capable of prolonging the survival and reducing the metastatic tumor burden of mice with a large tumor burden at the onset of therapy. This indicates that caution should be exercised in the use of M5076 tumors as a test model for chemotherapeutic agents, since the slightest contamination of an experimental drug with lipopolysaccharide would result in spurious positive results.

Animals↗
PubMed1984

A human melanoma line heterogeneous with respect to metastatic capacity in athymic nude mice.

The ability of the human A375 melanoma cell line to produce experimental and spontaneous in young BALB/c nude mice was examined. Cloned lines, obtained by isolation in semisolid agar, differed significantly (4/10 cloned lines examined, P less than or equal to .005) from the parent tumor line with regard to their ability to form lung tumor nodules subsequent to iv injection. Lines established from such lung tumor nodules were more metastatic than the parent line following both iv and sc injection. These results show that the human melanoma cell line used in these studies contained cells with diverse metastatic potential and suggest that metastasis in the nude mouse results from the preferential selection of metastatic subpopulations.

Animals↗
PubMed1984

Metastatic behavior of human tumor cell lines grown in the nude mouse.

The metastatic behavior of seven human tumor cell lines grown in young (3- to 4-week-old) nude mice was studied. Two cell lines were derived from malignant melanomas, one from a colon carcinoma, two from prostate adenocarcinomas, and two from renal adenocarcinomas. Many of the cell lines produced metastases after i.v. injection (experimental metastasis) and after s.c. transplantation (spontaneous metastasis) into young nude mice. The incidence of metastasis seemed dependent primarily on the biological characteristics of the individual tumor cell line. However, the incidence of metastasis of some tumor cell lines could be increased by isolation and establishment of variant sublines from secondary tumor deposits, by prolonged systemic administration of 17 beta-estradiol to suppress natural killer cell activity, and/or by use of an advantageous site of tumor implantation. Intrasplenic injection of tumor cells allowed the most dramatic overall expression of metastatic capacity in these cell lines, resulting in frequent and large metastases to liver, lungs, and the mesenteric, omental, and mediastinal lymph nodes.

Animals↗
PubMed1983

Follow-up of solitary autonomous thyroid nodules treated with 131I.

We studied the long-term effects of 131I therapy for solitary autonomous thyroid nodules on the size of the nodule and on thyroid function. Twenty-three patients with autonomous thyroid adenomas that had been treated with 131I from 4 to 16.5 years earlier (mean, 8.5) were examined, and their thyroid function was tested. In 12 patients (54 per cent), the nodules were still palpable, and in 2 they had increased in size. Eight patients (36 per cent) had become hypothyroid. The incidence of hypothyroidism was not related to nodule size or the level of thyroid function before therapy with 131I or to the total dose of 131I that had been given. We conclude that 131I therapy for autonomous thyroid adenoma often causes hypothyroidism and in many cases does not eradicate the offending nodule.

Adenoma↗
PubMed1983

Mononuclear phagocyte adherence in the presence of laminin. A possible marker of cellular differentiation.

The effect of laminin on the vitro adhesive behavior of mononuclear phagocytes was investigated. Laminin significantly inhibited the adhesion of guinea pig, mouse, and rat alveolar or peritoneal macrophages and of human peripheral blood monocytes. Adhesion of these cells was unaffected by similar concentrations of fibronectin. Experiments performed with monocytes maintained in culture showed that the degree of laminin-mediated inhibition of adherence was dependent on the state of differentiation of the cells: the less mature the monocytes, the greater the degree of inhibition. Laminin also reduced the attachment capacity of polymorphonuclear leukocytes isolated from human peripheral blood. These results suggest a possible role for laminin in the regulation of the passage of cells across the basement membrane during inflammation.

Animals↗
PubMed1983

Morphologic studies on a murine reticulum cell sarcoma (histiocytic sarcoma) of histiocytic origin and its metastases.

The M5076 tumor, a reticulum cell sarcoma of histiocytic origin that arose spontaneously in the ovary of a C57BL/6 mouse, is highly invasive and metastatic. Regardless of the site of the primary tumor, this neoplasm rapidly and preferentially metastasizes to the liver and spleen, killing the host. Numerous other organs also are involved, including the lungs and bone marrow. This tendency to metastasize to osseous tissues appears to be a characteristic of the M5076 tumor that rarely is found with other rodent neoplasms. However, these extrahepatic foci are evident only microscopically and are seen relatively late in the progression of tumor growth. We describe the sequential gross and microscopic lesions that develop in syngeneic mice during the metastatic spread of the M5076 tumor. Since viable tumor cells form small tumor colonies in most organs, we suggest that the gross pattern of metastasis, with the apparent predilection for hepatic tissue, is caused by variations in tumor cell proliferation rather than by distinctive patterns of neoplastic cell spread and entrapment.

Animals↗
PubMed1983

Comparative studies on the quantitative analysis of experimental metastatic capacity.

The purpose of these studies was to establish a procedure for determining the relative experimental metastatic potential of unrelated murine tumors. We used three tumors (the B16-F10 melanoma, which is syngeneic to the C57BL/6N mouse, and the K-1735 melanoma and the UV-2237 fibrosarcoma, which are syngeneic to the C3H/HeN mouse). Various numbers of tumor cells were injected into normal or immunosuppressed syngeneic recipients and into 3-week-old BALB/c nude mice. At appropriate intervals, the recipient mice were killed, and the metastatic burden was determined. The number of experimental metastases was not linearly correlated with cell input. Thus, simply comparing the incidence of metastasis resulting from the injection of one predetermined dose of tumor cells did not allow for determination of their relative metastatic capacities. More reproducible and meaningful results were obtained by introducing increasing numbers of viable tumor cells admixed with a constant number of nontumorigenic (X-irradiated) tumor cells serving as carrier. The incidence of metastasis by few or many injected cells is influenced by host factors such as immune status, and therefore determinations of the true metastatic nature of any given tumor necessitate the choice of an appropriate recipient.

Animals↗
PubMed1983

Tumor cell hybridization and neoplastic progression.

In the experiments reported here, I was unable to detect any fusion between host cells and transplanted tumor cells; however, spontaneous hybridization between tumor cells appears to occur in the B16 melanoma. This hybridization was demonstrated by mixing together B16-F10RR cells (universal fusers) and B16-F10 cells, allowing them to grow in close juxtaposition, and recovering putative hybrids in the appropriate selection media. The tumor cell-tumor cell composition of the resultant hybrids is inferred from the relative frequency of fusions, compared with the infrequency of tumor cell-host cell fusion when single populations of B16-F10RR cells were used, and by the chromosomal content of the hybrids. Definitive proof that hybridization occurs between both types of tumor cell rather than between a tumor cell and some other type of cell would require the use of a third biochemical marker on the unmarked tumor cells. I am now repeating these experiments using B16-F10 cells that exhibit resistance to the neomycinlike antibiotic G418. Nonetheless, it is not surprising to find that such closely related tumor cells fuse with one another. The efficiency of in vitro hybridization mediated by polyethylene glycol is increased when the hybridizing cells are histologically or developmentally related, so that B16 melanoma cells fuse more readily with one another than they do with unrelated cells such as UV-2237 cells (I. Hart, unpublished observations). Moreover, early hybridization protocols did not call for the use of fusogens, but merely the cocultivation of participating cells in the two-dimensional constraints of a tissue culture dish (e.g., Barski et al. 1961, Silagi 1967). Presumably, the increased contact between cells within a growing tumor mass would increase the likelihood of such spontaneous fusion. In vivo hybridization could play a significant role in neoplastic progression and variation in metastatic efficiency by at least two separate, but not necessarily mutually exclusive, mechanisms. First, fusion of two contiguous tumor cells would increase the chromosome content of the resultant single cell; this increase in ploidy could facilitate and heighten the apparent inherent genetic instability of neoplastic cells (Nowell 1976). Although segregation and chromosome loss may or may not be random or preferential in nature (Campbell and Worton 1981), the mere occurrence of such a phenomenon could also cause chromosomal disjunction and the possible extinction and reexpression of specific genes, which would lead to the independent variation and progression of different tumor cell characteristics in the manner cited by Foulds (1969).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Metastatic behavior of an adriamycin-resistant murine tumor.

The metastatic behavior of a murine fibrosarcoma (UV-2237M-ADMR) resistant to Adriamycin (ADM) (doxorubicin) was investigated. Subclones isolated from the UV-2237M-ADMR line, which originated from a single colony, generally displayed a similar degree of resistance to ADM (eight out of nine clones did not differ from this UV-2237M-ADMR line). In contrast, they differed significantly in their capacity to form lung colonies after i.v. injection (six of nine clones differed significantly from the UV-2237M-ADMR line, p less than or equal to 0.005, Mann-Whitney U test). The UV-2237M-ADMR cell line maintained resistance to ADM even after 17 weeks of growth in syngeneic mice, although a gradual decrease in resistance was observed over this time. Spontaneous metastases from the UV-2237M-ADMR tumor commonly retained resistance to ADM. Of 18 cell lines, each established from an individual lung nodule, 16 showed plating efficiencies in the presence of ADM comparable to that of the primary UV-2237M-ADMR tumor. The remaining two lines had partially reverted to the sensitive state. The i.v. administration of ADM significantly reduced the lung tumor burden of mice with ADM-sensitive UV-2237M tumors but failed to affect the lung tumor burden of mice with UV-2237M-ADMR tumors. The UV-2237M-ADMR tumor line, exhibiting as it does both drug-resistant and metastatic behavior, provides a useful model system with which to investigate the metastatic process and the development of drug resistance.

Animals↗
PubMed1983

Selective delivery of drugs encapsulated in liposomes: natural targeting to macrophages involved in various disease states.

In recent years, a considerable effort has been made to promote the use of liposomes as potential carriers for systemically administered chemotherapeutic agents. It is our belief that much of this proselytizing has ignored the normal and unavoidable fate of systemically administered liposomes, which is clearance by the reticuloendothelial system. Rather than attempting to avoid this phenomenon, we suggest that this occurrence could be advantageous for the selective delivery of agents to cells of the monocyte-macrophage series involved in various disease states.

Humans↗
PubMed1983

Isolation and preliminary characterization of an Adriamycin-resistant murine fibrosarcoma cell line.

A variant cell line (UV-2237-ADMR) resistant to the anthracycline antibiotic Adriamycin (Doxorubicin) was selected in vitro from the murine UV-2237 fibrosarcoma tumor cell line. Resistance to Adriamycin proved to be a stable characteristic of the UV-2237-ADMR line, whether the line was grown in vivo or in vitro. The UV-2237-ADMR line also exhibited increased resistance to N-trifluoroacetyladriamycin-24-valerate, daunorubicin, actinomycin D, amsacrine, mitomycin C, vinblastine, and vincristine but not to bleomycin. Cell-cell hybridization studies showed that the Adriamycin resistance is an incompletely dominant trait. Uptake and efflux studies with [14C]Adriamycin indicated that the resistance exhibited by the UV-2237-ADMR line was due to both reduced uptake of the drug and an increased active efflux.

Animals↗
PubMed1982

Biological diversity in metastatic neoplasms: origins and implications.

Whether neoplasms are unicellular or multicellular in their origin, the process of tumor evolution and progression can rapidly generate biological diversity. Metastases result from the survival and proliferation of specialized subpopulations of cells within the parent tumor. Metastases may have a clonal origin and different metastases may develop from different progenitor cells. However, as with the primary tumor, the origin of metastases is unimportant since the process of tumor evolution and progression can generate biological diversity within and among different metastatic foci.

Animals↗
PubMed1982

'Seed and soil' revisited: mechanisms of site-specific metastasis.

Clinical studies have shown that malignant tumors frequently show definite metastatic patterns. This tendency for neoplasms of a particular histologic type to metastasize to a specific organ is also a characteristic of experimental animal tumor systems. Mechanical entrapment, arrest determined by specific recognition between neoplastic cells and capillaries and organ-determined modulation of tumor growth have all been suggested as mechanisms that regulate this specificity. Experimental evidence for the role that each of these mechanisms plays in the regulation of metastatic patterns of transplantable rodent tumors is discussed in this review.

Animals↗
PubMed1982

Inhibition of cellular division of a murine macrophage tumor by macrophage-activating agents.

Although the murine reticulum cell sarcoma M5076 is highly malignant in vivo, in vitro it displays many of the functional characteristics of an activated macrophage, such as phagocytosis and tumor cytotoxicity. This study was designed to determine what effect macrophage-activating agents would have on the function and growth of M5076 cells. Exposure of M5076 tumor cells to substances that activate normal macrophages to the tumoricidal state rapidly and irreversibly induced cessation of cellular division. The treated tumor cells, however, retained the same characteristics as those of untreated M5076 cells in vitro with respect to viability and the activated macrophage functions of phagocytosis and tumor cytotoxicity. Even after a short exposure to lipopolysaccharide, the ability of M5076 cells, injected i.v. into syngeneic mice, to form tumor nodules was greatly reduced. These results indicate that a highly malignant tumor of macrophage origin, M5076, can be induced to cease cellular division while retaining the functional attributes of an activated macrophage. We speculate that the exposure of M5076 to macrophage-activating agents results in the induction of terminal differentiation of this tumor.

Animals↗