Course Of Tumor Growth Research Articles

Tumor Specific Immunity to Mouse Melanoma In Vitro

SummaryAn in vitro assay that measures the ability of mouse spleen cells to inhibit DNA synthesis (IDS) of syngeneic melanoma tumor cells was used in the evaluation of tumor immunity. The IDS assay was used in the measurement of both specific immunity mediated by spleen cells from tumor-bearing mice and nonspecific tumor cell growth inhibition mediated by normal spleen cells. Specific IDS was first demonstrable 2 weeks after injection of 106 B-16 tumor cells sub-cutaneously and persisted during advanced stages of disease. Changes in spleen cell IDS activity were correlated with changing mitogen reactivity during the course of tumor growth. A portion of the spleen cells mediating nonspecific IDS was removed by nylon wool filtration, but the effector cells exhibiting specific immunity were not removed by this procedure. Immune spleen cells did not need to synthesize DNA or divide to inhibit tumor cell DNA synthesis.

Cellular and humoral immune responses of mice during immunological enhancement of an allogeneic tumor.

Spleen cells obtained from C57BL/Ks (Ks, H-2d) mice carrying passively enhanced Sarcoma I (Sa I, H-2a) tumors were tested for alloantibody formation, lymphocyte blastogenesis, antibody-dependent cellular cytotoxicity, and cell to cell cytotoxicity. Assays were usually performed approximately 6 weeks after tumor inoculation. The results of these assays indicate that spleen cells from tumor-bearing mice are actively synthesizing alloantibody, but have a depressed blastogenic response to phytohemagglutinin and allogeneneic cells, and manifest no detectable cytotoxic activity in 51Cr release assays for antibody-dependent or cell to cell cytotoxicity. The absence of cell to cell cytotoxicity was specific and could not be attributed to the activity of suppressor cells acting in vitro, or to immunoglobulin secreted during the in vitro assay. These results indicate that Ks mice carrying immunologically enhanced Sa I tumors have a strong humoral response but a defective cellular response to the alloantigens of their tumors. These results are compatible with a mechanism of immunological enhancement which involves suppression of the development of the cellular immune response throughout the course of tumor growth.

Soluble tumor antigen-induced lymphocyte proliferation: effects of serum from normal and tumor-bearing mice.

The effect of serum from mice bearing methylcholanthrene-induced fibrosarcomas on the lympho-proliferative responses of their spleen and lymph-node cells to 3 M KCl-solubilized tumor antigens has been investigated. Low concentrations of serum (less than or equal to 2.5%) collected throughout the course of tumor growth were inhibitory. Normal sera collected from age-matched control mice were often slightly inhibitory, but to a significantly lesser extent at identical serum concentrations. The inhibitory effect of tumor-bearing serum was not limited to homologous tumors, but was also observed when cross-reacting syngeneic tumor antigens or serum from animals bearing other syngeneic tumors were added to the assay mixture. At the low concentrations used, tumor-bearing sera inhibited only tumor-antigen-induced proliferation, and not proliferation induced by T cell mitogens. The inhibitory effects of tumor-bearing sera on lympho-proliferative responses to soluble tumor antigens appear to be similar to the inhibition seen as "serum blocking" in other assays of tumor immunity.

Canine transmissible venereal sarcoma: electron microscopic changes with time after transplantation.

The structure of canine transmissible venereal sarcoma (CTVS) has been examined from 14 to 71 days after implantation. During early growth, the tumour appears to be composed primarily of loosely arranged, round cells and a few fibroblast-like cells. As the tumour mass increases, the round cells become tightly packed with highly interdigitating plasma membranes. The number of irregularly shaped round cells and fibroblast-like cells increases with increasing tumour mass. Collagen and reticular fibres can be found in early tumours, frequently in association with the round cells, and in regions devoid of fibroblast-like cells. During tumour regression, cellular degradation is evident in fibroblast-like and irregularly shaped cells as well as round cells. The data suggest that transformation may occur in the course of tumour growth, causing morphological change from round to fibroblast-like cells, and that CTVS is an undifferentiated round-cell sarcoma capable of differentiation in a fibroblastic direction. Also present, primarily in tumour cells from newborn dogs, are cytoplasmic lamellar arrays and crystalline virus-like structures, both previously described in other forms of tumor cells.

Correlation of suppressor cell development in parental and F1 hybrid mouse strains with the growth of a parental tumor in vivo.

Parental AKR/J, and AKB6F1 and AKD2F1 hybrid mice were injected subcutaneously with a spontaneously arising AKR/J tumor. The highly responsive AKB6F1 strain never exhibited any depression of immune functioning during the course of tumor growth and regression. The (AKR/J) intermediately responsive strain, while able to generate a successful anti-tumor response, did display a transient reduction of immunological capability, but only during the period tumor growth and not during tumor regression. Cells able to suppress antibody, but not cell-mediated responses, were found. The unresponsive AKD2F1 strain was characterized by both a marked depression of immune responsiveness, as well as the generation of suppressor cells to both antibody, and later, cell-mediated responses. Depression of immune responsiveness, and the generation of suppressor cells, appeared to correlate with the strength or weakness of the anti-tumor response in these strains of mice.

In Vitro Induction of Cytotoxicity against Syngeneic Mastocytoma and Its Suppression by Spleen and Thymus Cells from Tumor-Bearing Mice

P815 times 2 mastocytoma cells, when injected subcutaneously into syngeneic DBA/2 mice, induced T lymphocytemediated cytotoxicity in the mice. During the course of tumor growth this cytotoxic activity decreased and ultimately the tumor killed the mice. When spleen cells from mice with tumors in the early stages of growth were incubated in vitro with mitomycin C-treated tumor cells, specific cytotoxicity mediated by T lymphocytes was developed. In contrast, spleen cells, taken from mice with tumors at a later stage in their growth, did not develop cytotoxic activity. The unresponsiveness of spleen cells from mice with tumors in the latter stages of growth seemed to be due to the presence of suppressor cells since in vitro development of cytotoxicity by spleen cells from early tumor-bearing mice were inhibited by the addition of spleen cells or thymocytes from mice with progressively growing tumors. Normal spleen cells or thymocytes did not affect the response.

Effects of levamisole on in vivo and in vitro murine host response to syngeneic transplantable tumor.

The effects of levamisole were studied in vivo and in vitro on two murine tumors, B16 melanoma and adenocarcinoma 15091, syngeneic to the mouse strains used. Administration of levamisole before tumor transplantation enhanced the early appearance of neoplasms but did not affect the overall incidence or course of tumor growth as compared with that observed in controls given saline injections or animals given levamisole with lethally X-irradiated tumor cells. Administration of the drug 1 day before iv injection of tumor cells significantly reduced the incidence of pulmonary nodules, but if the drug was given 3 or 5 days before tumor challenge, the incidence of nodules was increased. Lymphocytes or macrophages from normal mice given levamisole had no effect on tumor cells in vitro, whereas lymphocytes incubated with levamisole in vitro enhanced tumor cell growth. When lymphocytes and tumor cells were mixed in vitro, lymphocytes from animals treated with the drug formed larger multicell clumps with tumor cells than did those from normal controls. We concluded that levamisole did not protect the mice against the tested tumors.

Lymphoproliferative disease in a cotton‐top marmoset after inoculation with infectious mononucleosis‐derived Epstein‐Barr virus

Injection of concentrated EBV derived from cells of the Kaplan line of infectious mononucleosis (IM) origin resulted in malignant lymphoproliferation in one out of three cotton-top marmosets 6 weeks after inoculation. Two additional animals receiving the same isolate after incubation with an antibody-containing human serum did not develop tumors. Inoculation of concentrated virus derived from the P3HR-1 line of Burkitt origin did not lead to lymphoproliferations in five marmosets. Three of these received non-neutralized, and two received neutralized P3HR-1 virus. The tumor obtained with the Kaplan isolate revealed characteristics of a lymphosarcome. It contained EBV-specific DNA. In addition, EBV-synthesizing lymphoblastoid lines were established from a tumorous lymph-node, as well as from the spleen of the diseased marmoset. Virus recovered from these lines transformed lymphocytes derived from spleens of healthy marmosets. The tumor-bearing animal developed low levels of anti-VCA antibodies during the course of tumor growth. These data demonstrate the oncogenic potential of EBV directly derived from cells of IM origin.

Serum factors modifying cell mediated immunity to rat hepatoma D23 correlated with tumour growth

Sera from rats bearing a progressively growing transplanted aminoazo-dye-induced hepatoma (hepatoma D23) have been examined for the presence of hepatoma D23-specfic antigen, antibody and immune complexes throughout the course of tumour growth. The levels of these factors have been correlated with the in vitro blocking and inhibition of cytotoxic lymph-node cells from immunized animals for cultured tumour cells. Sera from animals bearing small tumours (7-14 days after tumour implantation contain free tumour-specific antigen whilst immune complexes could not be detected. Although these sera were neither blocking nor inhibitory under the normal conditions of the test, when concentrated two and fourfold, inhibition but not blocking of lymph-node cell cytotoxicity could be detected. In comparison sera from animals bearing large tumours (24-28 days) blocked but did no inhibit in vitro lymph-node cell cytotoxicity and this correlates with the presence of tumour-specific immune complexes in antibody excess. Animals with intermediate-sized tumours had high levels of both blocking and inbibitory activity in the serum, these effects becoming apparent when neither free antibody nor free antigen could be detected. The relevance of these findings to the mechanism by which a growing tumour may escape specific cellular immune destruction is discussed.

Proliferation kinetics of a virus-induced sarcoma in the rat kidney

In experiments with Polyoma-virus-induced autochthonous fibrosarcomas of the rat kidney, the cell cycle parameters, the proliferative fraction, and the rate of cell loss were determined as essential factors for tumor growth. The results demonstrate a mean cell cycle time of 21·1 hr ± 12·8 by the 10th day, 26·3 hr ± 20·9 by the 20th day, and 29·8 hr ± 15·4 by the 30th day of growth. The proliferative fraction was between 39 and 50% and remained constant during the course of tumor growth. The critical factor in the great decrease in tumor growth rate was the rate of cell loss which, in large tumors, was up to about 100% of the rate of cell production. These results differ only from those obtained in most solid transplanted or spontaneous neoplasms with regard to the constancy of the proliferative fraction.

Microangiopathic haemolytic anaemia associated with hypercalcaemia in an experimental rat tumour.

Summary.A severe microangiopathic haemolytic anaemia develops during the course of tumour growth in rats bearing the solid Walker carcinosarcoma 256. Early changes of blood coagulation are the prolongation of the clotting and clot‐forming time in the thrombelastogram, a reduction of factor‐VIII activity and impaired platelet aggregation. Subsequent decrease of plasma fibrinogen and blood platelets indicate intravascular coagulation as the cause of the haematological changes. Fibrinogen turnover studies with homologous 131I‐fibrinogen showed a significantly shortened half time. Concomitant with the alterations of the clotting mechanism a decrease of plasminogen level as well as an increasingly prolonged euglobulin lysis time were found; these may be interpreted as the result of the fibrinolytic response to intravascular fibrin deposition. Histological examination of the animals’ organs demonstrated fibrin strands and large fibrin thrombi exclusively in the capillaries of the tumour. Simultaneously with the intravascular coagulation syndrome the animals develop a hypercalcaemia caused by a parathyroid hormone‐like substance elaborated by the tumour tissue. Since clinical reports point to an interrelation between thrombotic disorders and hyperpara‐thyroidism, the possible role of hypercalcaemia in triggering intravascular coagulation is briefly reviewed.

Studies on the mechanism and prevention of local recurrence of carcinoma at the suture line after colonic resection.

In order to elucidate the mechanism of the local recurrence at the suture line and to prevent it, the experimental studies were carried out using ascites tumor of rat. 1) In the course of tumor growth at the suture line, there were two different growth patterns spreading to the serosal surface in Yoshida sarcoma and to mucosal surface in AH-109A. 2) A linear relationship was found between tumor growth rate and number of tumor cells by observation of at 5 days sacrifice. 3) The experimental results offer ample evidence to occur easily the implantation of tumor cells at the suture line, resulting in the local recurrence in the varied shapes after colonic resection. 4) For prevention of it, the local irrigation by anticancer agent which brings about the decrease in number of tumor cells and direct effect may be of prophylactic value for local recurrence of carcinoma of the colon and rectum due to implantation of tumor cells.

Origin and development of carcinoma in the prostate.

Detailed histologic study of 45 cancerous prostate glands in 134 autopsies provided new information on the natural history of prostatic carcinoma. Origin of carcinoma was limited to one of two histologically distinct regions, but with no apparent predilection for the “posterior lobe” or sub capsular area. Carcinoma selectively originated from active gland epithelium rather than a trophic glands, and distinctive premalignant changes accompanied its origin. Evidence from volume distribution data suggests that there are not two types of prostatic carcinoma with different biologic potential, but a single species having slow growth rate with a logarithmic growth curve. The development of carcinoma in the gland follows predictable patterns, including early involvement of the capsule and perineural spaces. The later course of tumor growth is characterized by loss of differentiation and the ability to penetrate the capsule and periurethral stroma. This suggests a gradual increase in biologic malignant potential which is closely linked to tumor size. Probably the capacity for distant metastasis is almost limited to large carcinomas, and penetration of the gland capsule may be the most important predisposing factor.

Enzyme levels in the growing and spontaneously regressing flexner-jobling carcinoma. III. The breakdown of ATP to inosine and its effect on glycolysis

While ATP, ADP, and AMP-5 are broken down to inosine by both NRTH and RTH, AMP-3 is much more resistant to enzymic attack, but also reacts much more slowly in the adenylic kinase system. Its effect in supporting glycolysis by tumor homogenates in the presence of substrate amounts of HDP will largely be independent of the levels of the nucleotidases, nucleosidases, and deaminases concerned with the breakdown of ATP and its intermediates to inosine. On the other hand, the effect of ATP, ADP, and AMP-5 on the rate of glycolysis will be strongly dependent upon the levels of these enzymes. With RTH, lactic acid production will be considerably reduced. The critical issues are therefore the dephosphorylation rates of ATP, ADP, and AMP-5, as well as the deamination rate of AMP-5 versus the rephosphorylation of AMP-5 to ADP. Of the nucleotidases studied, ATPase and the over-all dephosphorylation of ADP are increased in RTH, while AMPase and adenosine deaminase increase both in the course of tumor growth and still further in the course of tumor regression. The question as to whether the increased rate of ADP-splitting is due to an increase of the adenylic kinase level or to that of a less specific apyrase has been left open. The nucleotidases investigated are inhibited by fluoride to various degrees. The enhancement of glycolysis by fluoride in HDP- and pyruvate-containing media is due to its manifold inhibitory effects, primarily concerned with nucleotidases and adenylic acid deaminase.

Factors Determining Radioresistance in Tumors

THE factors determining radioresistance in tumors are very numerous. They consist mainly in structural components of the tumor but arise as the result of many complicating conditions that occur in the course of tumor growth. A general conception of the subject may perhaps best be obtained by a review of various tumors and an inquiry into the nature of the resistance in each. Consideration of what may be accomplished by radiation in each of these groups may also be attempted. (1) Resistance due to adult character of stroma.—This form of resistance is observed in many types of sarcoma, osteogenic, neurogenic, chondrosarcoma. The stroma of many osteogenic sarcomas consists of bone, osteoid tissue, hyaline material, fibrous tissue, and often cartilage. All of these structures resist radiation and cannot be absorbed. There is a very great variety of such tumors so that the exact fate of anyone of them under radiation is difficult to predict, but in general they do not diminish in size under treatment. Their nu...

STUDIES BASED ON A MALIGNANT TUMOR OF THE RABBIT

The results obtained by intratesticular inoculation of a malignant tumor of the rabbit are presented in the form of a general summary covering the phenomena of growth and spontaneous regression of the tumor and the clinical evidence of disease in tumor animals. Under ordinary circumstances, growth is obtained by this method of inoculation in practically all animals, and the majority of them show metastases. The ultimate fate of tumor animals is variable. Spontaneous regression is of frequent occurrence, and apparent recovery may take place even after extensive metastases have developed. More often, the disease terminates fatally. The course of the disease may be fulminating in character with death occurring 6 to 7 weeks after inoculation, or it may be prolonged over a period of more than 6 months, but death usually occurs between 7 weeks and 3 months after inoculation. The symptomatology varies with the course of tumor growth but is in general that of a debilitating disease of an acute or chronic character in which the picture is frequently complicated by symptoms referable to mechanical causes or to one or more of the glands of internal secretion. The most prominent of these are due to the presence of metastases in the suprarenals or pituitary body, in which case symptoms of Addison's disease or diseases of the pituitary may be superimposed upon those attributable to the presence of extensive tumor growths. In the absence of such growths, however, the symptoms of suprarenal or pituitary involvement may dominate the picture.