cis-Diamminedichloroplatinum(II) (cis-DDP) is a well-known anticancer agent the use of which is limited by its toxicity. Since it has been demonstrated that selenium is able to combine with metals like cadmium and mercury and to reduce their toxicity, we decided to investigate whether it could reduce the toxicity of platinum. We treated fibrosarcoma-bearing mice with a combination of cis-DDP and selenium. The dose of 2 or 4 micrograms selenium/g animal weight had no effect on tumor growth. The i.p. injection of 16 micrograms cis-DDP/g led to early death of animals. The i.p. treatment of tumor-bearing animals with 2 or 4 micrograms of selenium reduced the early mortality induced by cis-DDP at a dose of 16 micrograms/g. Therefore, the addition of selenium allowed the administration of high doses of cis-DDP, which resulted in an improved antitumor effect. Clonogenic assays following drug exposure showed that selenium had no direct effect on tumor cells and did not modify the antitumor activity of cis-DDP. Electron microscopy showed reduced changes in renal cells when selenium was added to the cis-DDP treatment. Microanalysis showed no accumulation of either selenium or platinum within renal cells. These results suggest that the addition of selenium decreases the nephrotoxicity of cis-DDP.
Spleen cell suspensions of methylcholanthrene-induced tumor-bearing mice were tested for their ability to inhibit tumor growth in vitro. The level of cytostasis was correlated with tumor growth and disappeared rapidly after surgical removal of the tumor. Pretreatment by anti-Thy 1-2 antiserum and complement, or by carbonyl iron and a magnet, showed that adherent, non-T-cells were the main effector cells of the cytostatic antitumor effect. Thymus cells suspensions from tubor-bearing mice were not effective in inhibiting tumor growth. This cytostatic effect was not tumor specific, inasmuch as the same spleen cell suspension inhibited growth of tumor cells of different origin.
Summary— The subcellular distribution of halogenous molecules has been studied by SIMS microscopy in cultured cells of a human breast carcinoma (MCF‐7 cell line). Two instruments of microanalysis were used. A low lateral resolution ion microscope (SMI 300 CAMECA) and a prototype scanning ion microscope equipped with a cesium gun that gives high lateral resolution images. This apparatus has been developed by G Slodzian, in Onera Laboratories (Office National d'Etudes et de Recherches Aérospatiales). Molecules studied by low lateral resolution ion microscope were halogenous steroids: fluorometholone, triamcinolone, bromocriptine and bromoandrosterone. Analytical images show that the first two compounds are mainly localized in the nuclear structure of MCF‐7 cells whereas the last two molecules are localized in cytoplasm of these cells. Images were obtained with a resolution of 1 μm. With the scanning ion microscope, it is now possible to obtain images at the ultrastructural level. Four analytical images can be simultaneously obtained by a single scan of the imaged area, corresponding to a depth of erosion of the section of ten nm. The intranuclear distributions of three pyrimidine analogs, 5‐bromo‐2′‐deoxyuridine, 5‐iodo‐2′‐deoxyuridine and 5‐fluorouracil have been studied in phase S and M of MCF‐7 cells and these images have been compared to the distribution of sulfur, nitrogen and phosphorus. All these images have been obtained with a lateral resolution better that 100 nm.
The spleen cell population of adult C3H/He mice injected with a single sublethal dose of cyclophosphamide (CY) has been analyzed. An initial phase of spleen atrophy is followed by a considerable hypertrophy, and a progressive return to normal. During the phase of spleen atrophy, both B and T cell compartments are depleted, as estimated by the percentages of cells killed by anti-Thy 1-2 and anti-Ig antisera plus complement. During the stage of regeneration, the percentage of Ig + cells increases rapidly, and at the peak of splenomegaly, the percentage of Ig + cells is high whereas almost no Thy 1-2 + cells are detectable. Progresively, the spleen cell content returns to the original values. In thymo-deprived mice (nude mice and B mice) the percentage of null cells increases during the stage of regeneration, and B mice develop a large number of Ig +-bearing cells. Histologic examination shows that follicles (B-dependent areas) disappear 1 to 2 days before periarteriolar sheaths (T-dependent areas). At the peak of splenomegaly the architecture of the spleen is destroyed, and the interstitial tissue is composed of a dense and uniform layer of lymphoid cells. Progressively, the architecture returns to normal. In nude mice, the disappearance of follicles, and the appearance of a homogenous layer of lymphocytes has been observed. When analyzed for their pattern of electrophoretic mobilities (E.M.), spleen cells from untreated mice reveal two peaks of E.M. 0.80 and 1.15 micron x s-1 x V-1 x cm-1. After CY treatment, during the step of splenic hypertrophy, these two peaks disappear, and a single peak of intermediate mobility appears. In T-deprived mice, a single peak of the same mobility is detected at this stage. The nature and origin of cells which appear during the phase of regeneration are unclear, but their appearance in T-deprived mice argues against thymo dependence. These spleen cells have the ability to suppress the response of normal spleen lymphocytes to T and B cell mitogens.
Abstract Changes have been studied occurring in spleen and thymus lymphocytes, as well in their response to different mitogens, during the growth of Simian virus 40‐induced fibrosarcomas in hamsters. During tumor growth, the spleens of tumor‐bearing animals became considerably enlarged, and their content in lymphoid cells increased by 100%. Spleen lymphocytes responded normally or slightly higher than did normal controls to concanavalin A (Con A) stimulation when tumors were small, but their response gradually decreased to 30–40% of normal in animals bearing large tumors. These same cells, when cultured with normal lymphocytes in the presence of Con A, were without effect, or were mildly suppressive of the normal cellular response to Con A. The response to Iipopoly‐saccharide (LPS) decreased slightly. The thymus, on the other hand, became smaller and depleted of cells, and here too, the response to Con A gradually diminished. Macrophages were found in increased numbers in the enlarged spleens of tumor‐bearing animals. It is suggested that they played a role in the suppression of lymphocyte response to mitogens. Elimination of macrophages from cultures by the addition of carageenan resulted in an enhanced response of lymphocytes from tumor‐bearing animals to Con A. In addition, we found that carrageenan acts as a mitogen, most probably for B cells, and that when added to cultures containing LPS, a potentiation of the mitogenic response to LPS was obtained.
