Normal tissue antigens of tumor cells.
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Animals↗
Biomedical subjects
L Milas
Publications and source records attributed to L Milas.
Prophylaxis and treatment of experimental lung metastases in mice after treatment with liposome-encapsulated 6-O-stearoyl-N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine.
A new lipophilic muramyl dipeptide analog, 6-O-stearoyl-N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine, when incorporated in liposomes, was effective in both the prevention and eradication of experimental pulmonary metastases in mice. Multilamellar vesicles composed of synthetic phospholipids (phosphatidylglycerol and phosphatidylcholine) containing saturated myristoyl or unsaturated dioleoyl acyl chains were found to potentiate the antimetastatic activity of this glycopeptide. Prophylactic and therapeutic efficacy was observed against the three murine tumors tested: FSa, an immunogenic fibrosarcoma; NFSa, a nonimmunogenic fibrosarcoma; and B16 melanoma. Neither the administration of empty liposomes or free glycopeptide, nor their coadministration, had a significant antimetastatic effect. This approach is promising for the therapy of cancer metastases in humans, particularly in the prevention of metastatic seeding and in the treatment of micrometastases.
Acetylmuramyl-Alanyl-Isoglutamine↗
Metastatic abilities of murine sarcomas and carcinomas. II. Relationship to cell volume and DNA index.
The cell volume and DNA content were determined in 12 murine tumors and correlated with the ability of these tumors to metastasize spontaneously or to form lung nodules when injected i.v. The cell volume significantly correlated with spontaneous metastatic potential of investigated tumors (r = 0.683; 0.02 less than P less than 0.05) but not with the ability of tumor cells to form artificial metastasis. The DNA index significantly correlated with both spontaneous metastasis (r = 0.594; 0.02 less than P less than 0.05), and lung colonization (r = 0.631; 0.02 less than P less than 0.05). The DNA index barely correlated with the cell volume (r = 0.564; P = 0.10).
Animals↗
Enhancement by misonidazole of metastatic tumor nodule formation in the lungs of mice.
Investigations were performed to determine whether misonidazole, a hypoxic cell radiosensitizer, influences formation of tumor nodules in the lung of C3Hf/Kam mice and whether it affects the enhancement of tumor nodule formation caused by local thoracic irradiation (LTI). Cells from a chemically-induced fibrosarcoma (FSa) and a spontaneously-developed fibrosarcoma (NFSa) formed twice as many tumor colonies in the lungs of mice that received misonidazole as in untreated mice. The effect was observed only with doses of misonidazole of 1 mg/g or higher given within 2 days prior to i.v. injection of tumor cells. A similar twofold amplification of the effect of LTI occurred when 1 mg/g misonidazole was given 30 min before or 0.5 to 2 hours after irradiation. This increase was independent of the dose of LTI and the absolute number of tumor nodules in the lung. The mechanistic possibilities and clinical relevance of the misonidazole effect are discussed.
Animals↗
Antitumor and antimetastatic activity of the differentiating agent N-methylformamide in murine tumor systems.
N-Methylformamide (NMF), a cell-differentiating agent, was assessed for its antitumor activity against a fibrosarcoma (FSA), a hepatocarcinoma (HCA-I) and a mammary carcinoma (MCA-K), syngeneic to C3Hf/Kam mice. Tumors were grown as solitary tumors in the leg or as artificial or spontaneous micrometastases in the lung. NMF, at a dose of 300 mg/kg, was administered i.p. daily for 6 to 18 days. NMF slowed the growth of FSA and HCA-I tumors and totally inhibited the growth of the MCA-K tumor. However, the effect was transient; tumors resumed their pretreatment growth rate upon cessation of the treatment. Histologically, MCA-K tumors treated with NMF (300 mg/kg daily for six days) underwent considerable cell depopulation and reduction in mitotic activity. The number of artificial metastases, as well as the incidence and the number of spontaneous metastases, were markedly reduced by NMF. This resulted in a prolongation of the survival of mice that had artificial metastases of MCA-K tumor. The in vitro clonogenicity of MCA-K, but not of FSA or HCA-I cells, was reduced. However, in vivo reduction of MCA-K cell clonogenicity was minimal, if any. Thus, NMF is effective in restricting the growth of both solitary tumors and metastases, but the degree of response is highly dependent on tumor type.
Animals↗
Spontaneous metastasis: random or selective?
Spontaneous lung metastases from an infrequently metastasizing fibrosarcoma and a more highly metastatic mammary carcinoma showed no increased capacity for generating primary tumors with greater metastatic potential when transplanted into either normal or whole-body-irradiated syngeneic mice for up to six isotransplant generations. Rather, successive generations varied in their metastatic behavior, tending towards decreasing metastatic efficiency. These data support the view that spontaneous metastases are determined more by random survival of intravasated tumor cells than by the selection of preexisting metastatic cell variants.
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Concomitant development of granulocytosis and enhancement of metastases formation in tumor-bearing mice.
The experiments reported here show concomitant development of granulocytosis and enhancement of metastasis formation in C3Hf/Kam mice bearing NFSA fibrosarcoma. Both phenomena developed at approximately 2 weeks after s.c. transplantation of tumor cells, at a time when the tumor was approximately 10 mm in diameter. The number of granulocytes in the blood doubled approximately every 3.5 days, reaching about 30 times control levels shortly before the death of the mice. The magnitude of the metastasis enhancement formation by i.v. injection of tumor cells was three to four times the control value. Mice bearing NFSA had a significant increase in the number of endogenous CFUs. Plasma from NFSA-bearing mice and medium from cultured NFSA cells stimulated in vitro growth of granulocyte and macrophage colonies from normal bone marrow cell precursors, and induced granulocytosis upon i.v. injection into normal mice. This shows that NFSA tumor secretes factor(s) with potent granulopoietic activity. Injection of plasma from tumor-bearing animals followed by i.v. injection of NFSA cells did not lead to the enhancement of metastasis, implying that granulocytosis might be rather concomitant manifestation than a causative factor of the enhancement of metastasis formation. Importance of granulocytosis as a paraneoplastic manifestation during tumor growth is discussed.
Agranulocytosis↗
Multiple phenotypic divergence of mammary adenocarcinoma cell clones. II. Sensitivity to radiation, hyperthermia and FUdR.
We have shown that, with in vitro passage, subclones derived from clonal cell populations of 13762NF mammary adenocarcinoma undergo phenotypic drift and diversification in their cellular properties. Here we examine whether phenotypic divergence of 13762NF cell clones extends to therapeutic treatments used in eliminating mammary tumors and whether the apparent rates of phenotypic divergence vary for different treatments. Six subclones isolated from low passage clone MTF7 (T11; tissue culture passage 11) cells were compared to a similar number of subclones isolated from high passage clone MTF7 (T35; tissue culture passage 35) cells. Subclones derived from clone MTF7 (T11) were relatively homogeneous (not significantly different) in their inherent sensitivities to ionizing radiation, extrapolation coefficients and quasithreshold dose values (Do = 1.61-1.99 Gy; n = 0.89-3.42; Dq = 0-2.34). When the MTF7 (T11) subclones were examined for their sensitivities to 45 degrees C hyperthermic treatment, the inherent sensitivities and dose-response curve parameters (Do = 5.24-10.05 min; n = 1.08-10.47; Dq = 0.78-12.31) were heterogeneous (significantly different). In addition, the MTF7 (T11) subclones were heterogeneous (significantly different) in their sensitivities and dose-response curve parameters to 5-fluoro-2'-deoxyuridine (FUdR) treatment (slope = -0.70 to -1.59; y-intercept = 1.31 X 10(2) to 47.80 X 10(2]. The LD50 values for FUdR ranged from 14-150 nM for the MTF7 (T11) subclones. At high passage MTF7 (T35) subclones were heterogeneous in their dose-response parameters to ionizing radiation (Do = 1.17-2.05 Gy; n = 0.80-41.18; Dq = 1.79-4.94), hyperthermia (Do = 3.57-6.32 min; n = 2.08-13.54; Dq = 3.68-9.30) and FUdR (slope = -0.77 to -0.93; y-intercept = 4.64 X 10(2) to 8.83 X 10(2); LD50 = 50-160 nM). The results indicate that clonal cells diverge for distinct phenotypic properties at differing rates to form heterogeneous cell populations with unique sensitivities to various therapeutic treatments.
Adenocarcinoma↗
Studies on the antitumor activities of pyrimidinone-interferon inducers. Part 2. Potentiation of antitumor resistance mechanisms.
In continuation of studies on antitumor activities of pyrimidinone interferon inducers, we report here that 2-amino-5-bromo-6-mF-phenyl-4(3H)-pyrimidinone (ABmFPP) is similarly effective to 2-amino-5-bromo-6-phenyl-4-pyrimidinone (ABPP) in its ability to reduce the number of metastatic nodules of a spontaneous fibrosarcoma (NFSa) and a spontaneous mammary carcinoma (MCa-K) in the lungs of C3Hf/Kam mice. Both compounds were more effective when given to mice prior to, rather than after, intravenous transplantation of tumor cells. In studies on the mechanism of the antitumor activity of pyrimidinones, 2-amino-5-iodo-6-phenyl-4-pyrimidinone (AIPP) was used in addition to ABPP and ABmFPP. These agents were capable of activating peritoneal macrophages that thus became capable of lysing in vitro 3T12 transformed cells but not syngeneic BALB/c embryo fibroblasts. Also, these agents were capable of augmenting significantly the natural killer (NK) cell activity in the spleen of C3Hf/Kam mice. Spleen cells from treated mice admixed to NFSa cells inhibited in vivo tumor take of these cells when the admixture was injected subcutaneously. Pyrimidinones were also effective against the development of NFSa nodules in the lungs of T-cell deficient mice implying that the presence of T-cells is not a prerequisite for the induction of antitumor activity by these agents. A further observation was that pyrimidinone compounds reduced the metastasis formation enhancing effect of cyclophosphamide. Therefore, pyrimidinone interferon inducers exhibit an appreciable antimetastatic activity mediated through antitumor resistance mechanisms involving activation of macrophages and stimulation of NK-cells.
Animals↗
Treatment with cortisone plus heparin or hexuronyl hexoaminoglycan sulfates of murine tumors and their lung deposits.
Heparin, cortisone, and combination of these two drugs were used for treatment of solitary tumors and artificial lung metastases of the fibrosarcoma NFSA and the mammary carcinoma MCA-K in C3Hf/Kam mice. Heparin reduced the number of artificial metastases of both tumors, but it did not affect the s.c. growth of these tumors. Conversely, cortisone reduced both the number of artificial metastases and the growth rate of s.c. tumors. The effect of cortisone was not further influenced by heparin. Cortisone showed a tendency for causing enhancement of spontaneous metastases. In addition, two heparin analogs, hexuronyl hexoaminoglycan sulfates were studied against MCA-K solitary tumors and their spontaneous metastases. They were ineffective when given alone, and they did not influence the effect of cortisone on the s.c. tumor growth. However, they slightly reduced the cortisone-induced enhancement of spontaneous metastases.
Animals↗
Metastatic properties of murine sarcomas and carcinomas. I. Positive correlation with lung colonization and lack of correlation with s.c. tumor take.
The spontaneous metastatic properties of six sarcomas and seven carcinomas syngeneic to C3Hf/Kam mice were investigated and the correlation between spontaneous metastasis, the lung colony forming efficiency (LCFE) of i.v. injected tumor cells, and s.c. tumor take was determined. The incidence and number of spontaneous metastases in the lung were determined in mice that had primary tumors in the leg removed 17 to 120 days earlier, depending on tumor type. There was a significant positive correlation between spontaneous metastasis and LCFE when all 13 tumors were compared, but the significance was lost when carcinomas and sarcomas were considered separately. No significant correlation between spontaneous metastasis and the s.c. tumor take was observed. Also, no correlation was found between LCFE and the s.c. tumor take of carcinomas, but there was a strong inverse relationship between these two properties of sarcomas. The number of cells shed from primary tumors was estimated and found to be more extensive in tumors with higher metastatic properties. Thus, in general, highly metastatic tumors were characterized by a high LCFE and a significant cell shedding. Furthermore, LCFE was greatly increased by treatment of animals with cyclophosphamide and by admixing heavily irradiated tumor cells to viable cells, implying that local environmental factors are important in determining the establishment of tumor cell clonogens into metastasis.
Adenocarcinoma↗
Metastatic instability of murine tumor metastases: dependence on tumor type.
Fifteen metastatic lines derived in vivo from three syngeneic murine tumors, the sarcomas SA-NH and SA-4020 and the hepatic carcinoma HCA-I, were assessed for their stability of metastasis formation upon isotransplantation for several successive generations in syngeneic animals. Change in the metastatic phenotype was actively encouraged by a new procedure, the artificial selection for increased or decreased metastasis formation. Metastatic instability was dependent on tumor type, with five of six lines of tumor SA-NH, one of four lines of tumor SA-4020, and possibly one of five lines of HCA-I changing in lung metastasis formation. The instability of lung metastasis formation was also assessed by analyzing changes in the variance of the lines. Concomitant with a change in metastatic potential for lung metastasis, we observed a similar change for abdominal lymph node metastasis. We also report the selection of a less metastatic line. The variance of lung metastasis increased significantly only in the SA-NH lines. The instability of metastasis formation was attributed to genetic instability of metastatic cell lines.
Animals↗
Increase in radiosensitivity of lung micrometastases by hyperbaric oxygen.
Four-day-old artificial pulmonary micrometastases of two murine fibrosarcomas, designated FSA and NFSA, showed increased sensitivity to ionizing radiation by a factor of 1.13 when animals were exposed to hyperbaric oxygen breathing before and during irradiation, implying the presence of hypoxia in the micrometastases. At the time of irradiation the diameter of FSA and NFSA metastases was smaller than 200 and 100 microns, respectively, which, on the basis of oxygen diffusion, could not be responsible for hypoxia. It is assumed that hypoxia of micrometastases is passive, reflecting the radiobiological hypoxia of lung tissue that could exist under normal breathing conditions.
Animals↗
Enhancement of in vitro chemotherapeutic activity by dimethylsulfoxide.
The effects of the differentiation-inducing polar solvent dimethylsulfoxide (DMSO) on the in vitro response of murine hepatocarcinoma cells to cisplatinum, BCNU, and melphalan were investigated using the sister chromatid exchange (SCE) and cell survival assays. Growth of cells in medium containing 2 per cent DMSO enhanced drug-induced SCEs and cell kill. In order for the enhancement to occur, cells had to be exposed to DMSO for at least 48 h prior to drug treatment. The presence of DMSO during drug treatment did not affect cell response to the three chemotherapeutic agents. The enhancement of chemosensitivity was eliminated within 24 h of DMSO removal. These data suggest that the differentiation-inducing polar solvents may provide antineoplastic benefits when administered in combination with standard chemotherapeutic agents.
Animals↗
Effects of gamma irradiation on cultured rat and mouse microvessel endothelial cells: metastatic tumor cell adhesion, subendothelial matrix degradation, and secretion of tumor cell growth factors.
The effects of gamma-irradiation on the properties of microvessel endothelial cells were studied in vitro. After incubating confluent endothelial cell monolayers in low serum-containing medium for 24 h, the monolayers were irradiated with 137Cs. Survival of rat lung microvessel endothelial (RLE) and mouse brain microvessel endothelial (MBE) cells were similar after irradiation (Do = 2.17 and 1.75 Gy, Dq = 4.44 and 5.67 Gy, and n = 7.8 and 25 for RLE and MBE cells, respectively). We examined the effects of gamma-irradiation on endothelial cell morphology, adhesion of syngeneic rat lung or mouse brain metastasizing tumor cells, release of the subendothelial matrix-degrading enzyme heparanase, and secretion of soluble mitogenic factors that stimulated the growth of syngeneic metastatic tumor cells. The effects of gamma-irradiation were not apparent until several hours after irradiation, and by 24 h doses of greater than or equal to 10 Gy caused limited endothelial cell retraction and reorganization of the endothelial monolayer. By 24 h after irradiation there was also increased adhesion of metastatic tumor cells to RLE but not MBE cells. We also examined the effects of gamma-irradiation on the release from endothelial cells of enzymes that solubilize the subendothelial matrix. Radiation resulted in a significant increase in the release of matrix-degrading enzyme (heparanase) that solubilized [35S]-labeled heparan sulfate from subendothelial matrix. This was most pronounced in the 24 h sample from gamma-irradiated endothelial cells. Finally, we examined the gamma-irradiation-induced release of mitogenic factors from endothelial cells that could stimulate the growth of metastatic cells in serum-limiting medium. The medium from RLE but not MBE cells stimulated the growth of a rat mammary carcinoma cell line. The results suggest that gamma-irradiation of microvessel endothelial cells can affect the interactions of tumor cells with endothelial cells and their subendothelial matrix; these processes could facilitate metastasis formation in irradiated tissues such as the lung.
Adenocarcinoma↗
Influence of tumor transplantation methods on tumor growth rate and metastatic potential of solitary tumors derived from metastases.
This study was performed to determine whether the growth rate and metastatic potential of tumors generated by spontaneous lung metastases is influenced by transplantation methods. Three different tumors syngeneic to C3Hf/Kam mice were studied: the SA-NH and SA-4020 sarcomas and the hepatocarcinoma HCA-I. Solitary tumors in the legs of mice were generated by a single metastatic nodule taken at random from lung metastases, by a single metastatic nodule taken from each mouse with the highest number of metastases, by a mixture of cells from lung metastases taken randomly, or by a mixture of cells from primary leg tumors. These transplantation procedures were repeated for two to four isotransplant generations. Repeated isotransplants of primary tumors showed little if any change in the growth rate and metastatic spread. In contrast, primary tumors derived from spontaneous metastases frequently exhibited a decrease in their growth rate and an increase in metastatic potential. This was particularly frequent when tumors were established from single metastatic nodules taken randomly from the lung, or taken from lungs that contained the largest number of metastatic nodules. The magnitude of this change varied greatly among the three tumors studied. Increased metastatic formation in the lung was also frequently associated with slower growth of the primary tumors. Thus, transplantation methods used for establishing primary tumors have an important influence on the metastatic potential of tumor transplants.
Animals↗
Concomitant immunity to pulmonary metastases of a murine fibrosarcoma: influence of removal of primary tumor by radiation or surgery, of active specific immunization and treatment with Corynebacterium granulosum.
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Animals↗
Protective effects of WR-2721 against radiation-induced injury of murine gut, testis, lung, and lung tumor nodules.
WR-2721 (S-2-(3 aminopropylamino) ethylphosphorothioic acid) has been investigated for its ability to protect gut, lung, and testis, as well as fibrosarcoma (FSa) tumor nodules, in the lungs of mice from gamma-radiation injury. This compound greatly protected jejunum and testis epithelial cells. FSa micrometastases in the lung were protected to a lesser extent than jejunum and testis. Conversely, WR-2721 was not able to protect the lung against radiation-induced enhancement of tumor metastases formation generated by intravenously injected FSa cells.
Amifostine↗