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M F Poupon

Publications and source records attributed to M F Poupon.

161 records · Page 9Linked to original sources
PubMedDate not supplied

[Experimental model for metastasis of cecal origin].

The pre-selected tumor cells injection in the cecal wall of rat, seems to be a intermediate model between spontaneous evolution of a colon tumor and intrasplenic or direct intraportal injections. From rhabdomyosarcoma cells (RMS S4-MH-) which present the advantage to prudce up lymphatic, pulmonary and hepatic metastases after subcutaneously injection, first subcutaneously (S.C.), intrasplenic (I.S.) and intracecal sites were compared: In the I.C. model, tumor was obtained in 80% of case and the survival was nearly similar to S.C. model's one. The lymphatic metastases were more and more distal as the evolution and the liver metastases were rarely observed. The I.S. model increased quickly and there were always liver metastases; In the two cases, pulmonary metastases were rarely observed (0 and 2/5). With adenocarcinoma colonic cells (Pro b) I.C. injection in the rat, tumor were obtained in 48% of cases without peritoneal dissemination; lymphatic nodes metastases were observed in 80% of cases; liver metastases was obtained in one animal from metastasis pulmonary selection cell lines. The I.C. model allows to estimate the liver and lymphatic nodes part; improved, it would be used to test adjuvant therapies and immunoscintigraphy.

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Oncogene and MDR1 gene expression in rat rhabdomyosarcoma sublines of different metastatic potential.

The expression of various protooncogenes (myc, Ki-ras, Ha-ras, erbB, fms, sis, jun and fos) and a gene implicated in multidrug resistance (mdr1) was investigated in cell sublines, isolated from a rat rhabdomyosarcoma cell line, and in the corresponding tumors induced by injection of these cells into syngeneic rats. These cell lines and tumors, selected or not by treatment with chlorozotocin (Czt) or adriamycin (Adr), differed in their tumorigenicities and metastatic potentials. Our results showed that 1) an increased expression of some protooncogenes could be correlated with the metastatic potential of tumors; 2) such a correlation was not observed in the cultured cells from which these tumors were derived; 3) mdr1 expression, similarly to that of protooncogenes, was correlated with metastatic potential in all tumors except the Adr-selected tumors.

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Chlorozotocin-induced selection of autocrine and multidrug resistant variants from a rat rhabdomyosarcoma.

The ability of tumor cells to develop simultaneous resistance to structurally different cytotoxic drugs constitutes a major problem in cancer chemotherapy. We previously described that a nitrosourea, chlorozotocin (CZT), increased in vivo the pulmonary metastatic dissemination of a rat rhabdomyosarcoma and enhanced in vitro the cloning efficiency (CE) of the same tumor cell line. The selection procedure for chlorozotocin-selected cell lines (R1 to R9 lines), by in vitro CZT-treatment and cloning assay, indicated that 2.5% of the parental cell line was a CZT-resistant subpopulation. This subset acquired, in the course of the selection steps in semi solid medium, a multidrug-resistant phenotype. In a stem cell assay, the resistance of the R9 line was increased 10-fold for adriamycin (ADR) and up to 2 fold for cisplatinum. In comparison, C8 control line sensitivity to ADR did not change significantly. This resistance did not affect the non clonogenic population, as shown in a monolayer proliferation assay. Re-exposure of R (R1-R9) lines to CZT or initial CZT contact with C lines transiently but consistently increased the CE; however, clonogenicity remained stable, and this was also observed when deticene, another alkylating drug, was used instead of CZT. Moreover, the CZT-selected R9 line easily proliferated in serum-free medium in the presence of transferrin and insulin, whereas serum was necessary to maintain the growth of the parental cell line or C lines. Finally, we show that in vitro selection of variants, by both resistance to CZT and cloning, led to the isolation of a multi-drug resistant subpopulation, serum independent for its proliferation - two properties associated with progressive malignancy.

Alkylating Agents↗
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DNA transfection affects the metastatic capacity of tumour cells.

A rat rhabdomyosarcoma clonal line RMS/8 was cotransfected with genomic DNA of procaryotic or eucaryotic origin and neomycin resistance plasmid pKOneo. The lung colonizing and metastatic capacity of transfected cells was evaluated. When col- meta- RMS/8 cells were transfected, an increase in lung colonizing but not in metastatic ability was observed. The DNA transfection of col+ meta- RMS/8 cells led to an enhancement of metastatic potential. These effects were independent of the origin of donor genomic DNA but were closely related to the transfection efficiency. It is suggested that DNA transfection destabilized the recipient genome, thus leading to an increased heterogeneity which potentially favours metastasis. The mock-transfected col+ meta- RMS/8 cells also exhibited an increased metastatic capacity. The non-specific effects of DNA transfection and of transfection procedure per se should therefore be taken into account in gene transfer studies of metastasis.

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Decreased rat rhabdomyosarcoma pulmonary metastases in response to a low methionine diet.

Many Experimental and human tumor cell lines have been previously described as being dependent upon exogenous methionine for their in vitro proliferation. The rationale of the experiments described herein was to decrease the in vivo growth of malignant tumors by reducing the exogenous methionine available in diets fed to Wistar AG rats bearing the highly metastatic rhabdomyosarcoma, RMS-J1. The methionine content in the diet was reduced either by replacing casein (diet 1) with soybean protein (diet 4), or by lowering the amount of soybean protein in the diet (from 23 g/100 g to 12 g/100g) (diet 5), or by using a crystalline amino acid-defined mixture as the source of protein (diet 7). In the latter diet homocysteine replaced methionine and allowed the survival of the animals. Diet 4 significantly reduced the mean number of lung metastases without affecting the primary tumor growth. Treatment of RMS-J1 bearing rats with diet 5 led to the decrease of pulmonary invasion (78 and 21 median lung metastases, respectively, in control and treated groups). This diminished metastatic dissemination resulted from the reduced methionine consumption: the lowered casein content in diet 3 (10 g/100 g) as compared to diet 1 (23 g) did not alter primary tumor growth or the amplitude of lung invasion. Moreover, the addition of methionine to diet 5 prevented the diminution of the median number of lung metastases. Replacement of methionine with homocysteine in the crystalline amino acid-defined mixture (diet 7) fed to RMS-J1 bearing rats led to a limited retardation of primary tumor growth (less than 10%) and to a significant decrease in pulmonary invasion: the median number of pulmonary metastases was 28 and 9 for control and treated rats respectively.

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Altered distribution of copper (64Cu) in tumor-bearing mice and rats.

64Cu was injected in the form of CuCl2 either by subcutaneous or by intraperitoneal route, and its distribution inside different organs was analyzed in 5 different tumor models, 4 in mice and 1 in rats. In all organs tested (blood, liver, kidneys, spleen, intestine, muscle, and tumor) no significant differences were observed in the results obtained after either injection route. All tumors analyzed (Krebs ascite, intestinal Leiomyo sarcoma, human tumor, mammary adenocarcinoma, either spontaneous or chemically induced) contained a relatively high concentration of 64Cu. For all tumor models tested, the 64Cu distribution was altered as compared with that of the corresponding control animals.

Adenocarcinoma↗
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In vitro electron microprobe of carcinogenic nickel compound interaction with tumor cells.

Some nickel compounds (Ni3S2,Ni) induce tumours in muscle, while others have no effect (NiO). It has been suggested that the carcinogenicity of nickel is related to its penetrating power (phagocytosis) in transformed cells. The penetration of various nickel salts into cultured rhabdomyosarcoma cells (RhC) was studied. Electron microscopy and microanalysis were used to study the ultrastructure and intracellular localization of nickel in ultra-thin sections. Nickel subsulfide (Ni3S2) and nickel oxide (NiO) penetrated into cells and were concentrated in vacuoles, exhibiting a particular affinity for membrane structure. They subsequently appeared to be eliminated in the extracellular medium. Colloidal nickel and iron carbonyl, on the other hand, did not penetrate these cells. Various tumoral and normal cells were compared for their ability to phagocytose Ni3S2; it was found that these compounds penetrated only RhC and macrophages. In vivo studies have demonstrated the various carcinogenic properties of nickel and two of its salts. Comparison with in vitro results suggests that the phagocytosis of nickel compounds is not directly related to eventual induction of a tumour. No nuclear localization could be detected, but a mechanism for concentration and elimination of these compounds, and especially for rhabdomyosarcoma tumour cells, was suggested.

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Induction of suppressor cells in mice by cyclophosphamide.

The injection of a single sublethal dose of cyclophosphamide (CY) into adult C3H/He mice induced splenic atrophy followed by considerable hypertrophy. During the phase of splenomegaly, the in vitro reactivity of spleen cells to the mitogens phytohaemagglutin and lipopolysaccharide was drastically decreased. Furthermore, the spleen cell population from CY-treated mice contained suppressor cells capable of inhibiting the in vitro reactivity of normal lymphocytes to these mitogens. After the removal of adherent cells, the suppressive activity was completely absent from the remaining fraction. The suppressive activity was also abolished after treatment of spleen cells with anti-immunoglobulin antiserum plus complement (C). After treatment with anti-Thy 1-2 antiserum plus C, the suppressive activity was not modified. Nude mice, B mice, young and old NZB mice, also developed suppressor cells with similar functional characteristics when treated with CY. However, in Nude mice the suppressor cells were not adherent and did not bear surface Ig. After fractionation of spleen cells by velocity sedimentation, the suppressive activity was detected in the fastest fraction with a velocity over 5 mm/h.

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Establishment and characterization of five human small cell lung cancer cell lines from early tumor xenografts.

Five small-cell lung carcinoma (SCLC) cell lines were established from xenografted tumor lines. These tumor lines were established after transplantation into nude mice of primary tumors or metastatic foci obtained surgically, from untreated (IRSC-2M, IRSC6M, IRSC-10M and IRSC-61M) or treated patients (IRSC-74M). They were then set-up in culture as parallel cell lines. Histologically, these tumor lines were classified as being of the classic (IRSC-2M, IRSC-10M and IRSC-61M) or intermediate type (IRSC-6M and IRSC74M). Four of these 5 SCLC cell lines grew as floating cell aggregates, while one (IRSC6M) grew as an adherent cell monolayer. Growth rates were slow (doubling times ranged between 120 and 194 h) but could be accelerated (67 to 144 h) by cultivating cells in medium mixed (v/v) with self-conditioned medium. Electron microscopical examination revealed that all SCLC cell lines contained dense core granules, characteristic of their neuroendocrine origin. These cell lines formed colonies in agarose with colony forming efficiencies ranging from 0.02-0.36%. The classic-type cell lines retained their tumorigenic capacity when re-injected intracranially into naive nude mice, whereas the intermediatetype cells did not. Cytogenetic analysis confirmed the human origin of SCLC xenografts and cultured cell lines. Various numerical and structural chromosome abnormalities were found, with deletion in the short arm of chromosome 3 being the most common (4 of the 5 cell lines). Deletions in or loss of the chromosome 10 were also observed. Oncogene expression was studied in 3 representative cell lines (IRSC-10M, IRSC-2M and IRSC-74M). L-myc was overexpressed only in IRSC-74M, while the GRP gene was overexpressed in the classic (IRSC-2M and IRSC-10M) but not in the intermediate-type cells (IRSC-74M). The Ki-ras oncogene was overexpressed in the 3 cell lines, while c-myc, N-myc, Ha-ras, N-ras, erb B2 and sis were not detected in any of them. The 3 cell lines weakly expressed the MDR1 gene, while the GST-pi gene was not expressed. These cell lines constitute a multifaceted well-characterized in vitro model for studying the biology of these phenotypically diverse cancer cells.

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Antitumor activity of the new vinca-alkaloid S 12363 alone or in combination with verapamil on a human multidrug resistant renal carcinoma xenograft.

We have established a model of human renal cell carcinoma, Kgg2, transplanted into athymic nude mice which expressed P-glycoprotein (P-gp) (detected by flow cytometry) and a high level of mRNA transcript of mdr1 gene (Northern blot analysis). We have evaluated the antitumor activity of a new highly potent vinca-alkaloid derivative, S 12363, in comparison with the activity of the reference compound vinblastine (VLB), when used alone or in combination with verapamil (VRP). The influence of the calcium influx blocker verapamil on the activity of the combination of S 12363 with adriamycin (ADR) was also determined. The results showed that S 12363 at a dose of 0.05 mg/kg/day, administered alone by intraperitoneal route daily on days 1 to 5, induced a tumoral regression of 50% during the first days after treatment. This effect was potentialized by simultaneous treatment with verapamil at 20 mg/kg/day for 5 days, leading to a long-term reduction of 70% of tumor growth. Vinblastine at a dose of 0.4 mg/kg/day administered alone or in combination with verapamil, using the same protocol, was less efficient. The association of S 12363 at 0.075 mg/kg/day (on days: 1-5, 11, 21 and 31), adriamycin at 2 mg/kg/day (on days: 11, 21 and 31) and verapamil at 20 mg/kg/day (on days: 0-5, 11, 21 and 31) induced an important reduction of tumor growth of 80% at the end of the experiment. In conclusion, the new vinca-alkaloid derivative S 12363 could present a therapeutic advantage over the reference compound vinblastine in the treatment of renal cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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Lack of inhibition by mouse alpha-foetoprotein (AFP) of in vitro induced lymphocyte blastogenesis.

Mouse amniotic fluids (MAF) were tested for their inhibitory effect on the transformation of lymphocytes by concanavalin A, phytohemagglutinin or lipopolysaccharide of Escherichia coli, and on mixed lymphocyte cultures. Eight of the thirteen samples tested contained inhibitory activity equal or superior to 50 % of the controls. Pure preparations of mousealpha-foetoprotein (AFP) were obtained from these or other MAF-pools by immunoadsorption and/or by affinity chromatography on oestradiol-Sepharose. None of the isolated samples of AFP, whether originating from immunosuppressive MAF-pools or from pools lacking activity, exhibited a significant inhibitory effect on the in vitro transformation of lymphocytes. The suppressive properties of the MAF samples and the non-suppressive activity of samples of pure AFP were not affected by the addition of oestradiol-17 beta or after removal of endogenous oestrogens by exhaustive dialysis against 15 % dioxan solutions.

Amniotic Fluid↗
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[Suppressive cells induced by cyclophosphamide in the spleen of C3H mice].

The spleen cell population of C3H/He mice injected with a single sublethal dose of cyclophosphamide (CY) was analysed. An initial atrophy was followed by a considerable hypertrophy and a progressive return to normal. During the phase of spleen atrophy, both B and T cell compartments were depleted. During regeneration, the percentage of Ig+ cells increased rapidly, and at the peak of splenomegaly, the percentage of Ig+ cells was high while no Thy1-2+ cells were detectable. The peculiar points of histology were disappearance of normal T and B compartments, substituted by a layer of lymphoid cells. During the phase of splenectomegaly, the in vitro reactivity of spleen cells to the mitogens PHA and LPS was drastically decreased. Furthermore, the spleen cell population from CY treated mice contained suppressor cells, capable of inhibiting the in vitro reactivity of normal lymphocytes to these mitogens and the multiplication of tumour cells in culture. These cells were adherent, Ig+, Thy1-2- cells. They developed in CY treated T deprived mice. After velocity sedimentation the suppressive activity was detected in the 6 mm/h fraction.

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Efficiency of orthotopic xenograft models for human colon cancers.

It is feasible to graft human colon cancer tissue into immuno-deficient nude mice, in order to maintain these tumors in vivo. Analysis of the properties tumors under such conditions might increase our knowledge of their biological characteristics. Xenografts are usually implanted into subcutaneous tissue, a site easily accessible for both graft procedure and observation of tumor growth. However these subcutaneous tumors are usually non-invasive and fail to metastasize. To override these limitations we, as others, have tried to improve the tumor xenograft model by transplanting tumors into their original location, designated as the orthotopic site. Transplanted into the cecum of nude mice, human colon cancers were frequently locally invasive and developed liver metastases. These transplantations may be done by injection of colon cancer cell suspensions into the cecal wall. Alternatively, orthotopic implantations of histologically intact tissue were performed and the thus-obtained tumors were more metastatic than tumors obtained after tumor cell injections. The chemosensibility of tumors xenografted into their orthotopic site was different from that of their subcutaneously implanted counterpart. This, added to the enhancement of invasive and metastatic properties, leads us to conclude that colon cancer xenografted into the caecum might be more representative of the clinical situation. We have reviewed the literature and report on the possibilities and limitations different models of colon cancer in vivo.

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Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure.

To elucidate the reasons for glycolytic deviation commonly found in brain tumors, hexokinase (HK) activity, mitochondria-HK binding, oxidative phosphorylation and mitochondrial ultrastructure were studied in 4 human xenografted gliomas. Lactate/pyruvate ratios were increased 3-4 fold and HK activity was of 2-4 fold lower than that of normal rat brain tissue, used as the control. The mitochondria-bound HK (mHK) fraction varied considerably and represented 9 to 69% of the total HK of that normal rat brain. The respiratory activity of glioma mitochondria, assessed by polarography and spectrophotometry, was within the normal range. However, the mitochondrial content of gliomas was lower than in the rat brain tissue, as revealed by the markedly decreased, activities of two unrelated mitochondrial enzymes, cytochrome c oxidase and citrate synthase in glioma homogenates. Electron microscopical studies confirmed the reduced number of mitochondria in 3 out of the 4 gliomas. Profound alterations of mitochondrial ultrastructure, namely of cristae and matrix densities, were observed in the 4 gliomas. The intercrista space was wider in all gliomas and the crista area was larger in 3 out of the 4 gliomas than in normal rat brain. Finally, the outer membrane of glioma mitochondria interacted intimately and extensively with the rough endoplasmic reticulum (RER) and/or nuclear membrane. These results suggest that, because of the very low content of normally functioning mitochondria, gliomas shift their energy metabolism towards a high-level glycolysis to generate their cellular ATP supply, probably through RER-mitochondria interactions and transformation-dependent redistribution of particulate HK from non-mitochondrial to mitochondrial receptors.

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Growth dependency of human colon cancer xenograft on organ environment is related with their original clinical stage.

The ability of cancer cells to metastasize might depend on their reduced dependency on the originating tissue. To test this hypothesis, 10 human colorectal carcinomas (CRC) were implanted either onto nude mouse caecum wall (orthotopic site), or into the subcutaneous tissue (ectopic site), and their growth in these sites compared. Prognostic factors were studied: Astler-Coller modified Dukes's stage, loss of chromosome 17p and/or 18q, and their TP53 gene. Early stage CRC [B2 (n = 3) and C1 (n = 1)] were found to grow 1.7 to 3.6 times (p < 0.05, p < 0.008 respectively) more rapidly in the caecum than in subcutaneous tissue. Metastatic stage CRC [C1 (n = 1), C2 (n = 2) or D (n = 3)] grew similarly in both sites, and more slowly than those of the first group. No relationship was found between growth rates, TP53 mutations or karyotypes. Growth rate of non metastatic cancers was slowed down by implantation in a foreign tissue whereas growth of metastatic tumours was similar in both sites, indicating that they do not recognize or need tissue growth factors.

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