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1. Macrophage phenotypes and monocyte subsets after destabilization of the medial meniscus in mice

Author

Utomo, L, Fahy, N, Kops, N, van Tiel, S T, Waarsing, J H, Verhaar, J A N, Leenen, P J M, van Osch, G J V M, Bastiaansen Jenniskens, Y M, Utomo, L, Fahy, N, Kops, N, van Tiel, S T, Waarsing, J H, Verhaar, J A N, Leenen, P J M, van Osch, G J V M, and Bastiaansen Jenniskens, Y M

Abstract

Macrophages play an important role in the development and progression of osteoarthritis (OA). The aim of this study was to identify macrophage phenotypes in synovium and monocyte subsets in peripheral blood in C57BL/6 mice by destabilizing the medial meniscus (DMM), and the association of macrophage subsets with OA features. DMM, sham, and non-operated knees were histologically assessed between 1 and 56 days for macrophage polarization states by immunohistochemistry (IHC), cartilage damage, synovial thickening, and osteophytes (n=9 per timepoint). Naive knees (n=6) were used as controls. Monocyte and polarized synovial macrophage subsets were evaluated by flow cytometry. CD64 and CD206 levels on IHC were higher at early timepoints in DMM and sham knees compared to naive knees. iNOS labeling intensity was higher in DMM and sham knees than in naive knees from d3 onwards. CD163 expression was unaltered at all timepoints. Even though macrophage polarization profiles were similar in DMM and sham knees, only in DMM knees the presence of iNOS and CD206 associated with synovial thickness, and CD163 staining inversely correlated with osteophyte presence. At day 14, monocyte subset distribution was different in peripheral blood of DMM compared to sham mice. In conclusion, monocyte subsets in blood and synovial macrophage phenotypes vary after joint surgery. High levels of iNOS+ , CD163+ , and CD206+ cells are found in both destabilized and sham-operated knees, and co-existence with joint instability may be a requirement to initiate and exacerbate OA progression. This article is protected by copyright. All rights reserved.

Published
2021

4. Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-alpha-based isolated hepatic perfusion

Author

van Etten, B, de Vries, M R, van IJken, M G A, Lans, T E, Guetens, G, Ambagtsheer, G, van Tiel, S T, de Boeck, G, de Bruijn, E A, Eggermont, A M M, ten Hagen, T L M, van Etten, B, de Vries, M R, van IJken, M G A, Lans, T E, Guetens, G, Ambagtsheer, G, van Tiel, S T, de Boeck, G, de Bruijn, E A, Eggermont, A M M, and ten Hagen, T L M

Abstract

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-alpha) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-alpha in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-alpha contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastases model we studied three different tumours: colon carcinoma CC531, ROS-1 osteosarcoma and BN-175 soft-tissue sarcoma which exhibit different degrees of vascularisation. IHP was performed with melphalan with or without the addition of TNF-alpha. IHP with melphalan alone resulted, in all tumour types, in a decreased growth rate. However in the BN-175 tumour addition of TNF-alpha resulted in a strong synergistic effect. In the majority of the BN-175 tumour-bearing rats, a complete response was achieved. In vitro cytoxicity studies showed no sensitivity (CC531 and BN-175) or only minor sensitivity (ROS-1) to TNF-alpha, ruling out a direct interaction of TNF-alpha with tumour cells. The response rate in BN-175 tumour-bearing rats when TNF-alpha was coadministrated with melphalan was strongly correlated with drug accumulation in tumour tissue, as only in these rats a five-fold increased melphalan concentration was observed. Secondly, immunohistochemical analysis of microvascular density (MVD) of the tumour showed a significantly higher MVD for BN-175 tumour compared to CC531 and ROS-1. These results indicate a direct relation between vascularity of the tumour and TNF-alpha mediated effects. Assessment of the tumour vasculature of liver metastases would be a way of establishing an indication for the utility of TNF-alpha in this setting.

Published
2003

10. Poster Abstracts

Author

Littger, Ralf, primary, Alke, Alexandra, additional, Tewes, Bernhard, additional, Gropp, Felix, additional, Asai, T., additional, Watanabe, K., additional, Kuromi, K., additional, Kurohane, K., additional, Ogino, K., additional, Taki, T., additional, Tsukada, H., additional, Nakayama, J., additional, Oku, N., additional, Babai, I., additional, Matyas, G., additional, Baranji, L., additional, Milosevits, J., additional, Alving, C. R., additional, Bendas, G., additional, Rothe, U., additional, Scherphof, G. L., additional, Kamps, J. A. A. M., additional, Kessner, S., additional, Carafa, M., additional, Di Stefano, A., additional, Sozio, P., additional, Cacciatore, I., additional, Mosciatti, B., additional, Santucci, E., additional, Choice, E., additional, Harvie, P., additional, Galbraith, T., additional, Zunder, E., additional, Dutzar, B., additional, Anklesaria, P., additional, Paul, R., additional, Cocquyt, J., additional, De Cuyper, M., additional, Van der Meeren, P., additional, Cruz, M. E. M., additional, Gaspar, M. M., additional, Silva, M. T., additional, Dathe, M., additional, Nikolenko, H., additional, Wessolowski, A., additional, Schmieder, P., additional, Beyermann, M., additional, Bienert, M., additional, Santos, N. Dos, additional, Cox, K. A., additional, Allen, C., additional, Gallagher, R. C., additional, Ickenstein, L., additional, Mayer, L. D., additional, Bally, M. B., additional, Fischer, S., additional, Margalit, R., additional, Freisleben, H.-J., additional, Garidel, P., additional, Chen, H. C., additional, Moore, D., additional, Mendelsohn, R., additional, Keller, M., additional, Hildebrand, A., additional, Blume, A., additional, Girão da Cruz, M. T., additional, Simões, S., additional, Pedroso de Lima, M. C., additional, Graser, A., additional, Nahde, T., additional, Fahr, A., additional, Müller, R., additional, Müller-Brüsselbach, S., additional, Cudmore, S., additional, O'Mahony, D., additional, Hoving, S., additional, van Tiel, S. T., additional, Seynhaeve, A. L. B., additional, Ambagtsheer, G., additional, Eggermont, A. M. M., additional, ten Hagen, T. L. M., additional, Høyrup, P., additional, Jensen, S. S., additional, Jørgensen, K., additional, Iden, D., additional, Kuang, H., additional, Mullen, P., additional, Jacobs, C., additional, Roben, P., additional, Stevens, T., additional, Lollo, C., additional, Ishida, T., additional, Maeda, R., additional, Masuda, K., additional, Ichihara, M., additional, Kiwada, H., additional, Jung, K., additional, Reszka, R., additional, Kaiser, N., additional, Ohloff, I., additional, Linser-Haar, S., additional, Massing, U., additional, Schubert, R., additional, Kan, P., additional, Tsao, C. W., additional, Chen, W. K., additional, Wang, A. J., additional, Kimpfler, A., additional, Gerber, C., additional, Wieschollek, A., additional, Bruchelt, G., additional, Kobayashi, T., additional, Okada, Y., additional, Sone, S., additional, Harashima, H., additional, Maruyama, K., additional, Kondo, Masayo, additional, Lee, Chun Man, additional, Tanaka, Toshiyuki, additional, Su, Wei, additional, Kitagawa, Toru, additional, Ito, Toshinori, additional, Matsuda, Hikaru, additional, Murai, Toshiyuki, additional, Miyasaka, Masayuki, additional, Junji, Kimura, additional, Kondo, Masami, additional, Asai, Tomohiro, additional, Ogino, Koichi, additional, Taki, Takao, additional, Tsukada, Hideo, additional, Baba, Kazuhiko, additional, Oku, Naoto, additional, Koning, G. A., additional, Wauben, M. H. M., additional, Vestweber, D., additional, Everts, M., additional, Kok, R. J., additional, Schraa, A. J., additional, Molema, G., additional, Schiffelers, R. M., additional, Storm, G., additional, Kristl, J., additional, Šentjurc, M., additional, Abramović, Z., additional, Landry, S., additional, Perron, S., additional, Bestman-Smith, J., additional, Désormeaux, A., additional, Tremblay, M. J., additional, Bergeron, M. G., additional, Madeira, C., additional, Loura, L. M. S., additional, Fedorov, A., additional, Prieto, M., additional, Aires-Barros, M. R., additional, Marques, C. M., additional, Simões, S. I., additional, Cruz, M. E., additional, Cevc, G., additional, Martins, M. B., additional, Moreira, J. N., additional, Gaspar, R., additional, Allen, T. M., additional, Esposito, C., additional, Ortaggi, G., additional, Bianco, A., additional, Bonadies, F., additional, Malizia, D., additional, Napolitano, R., additional, Cametti, C., additional, Mossa, G., additional, Endert, Gerold, additional, Essler, Frank, additional, Lutz, Silke, additional, Panzner, Steffen, additional, Pastorino, F., additional, Brignole, C., additional, Pagnan, G., additional, Moase, E. H., additional, Ponzoni, M., additional, Pavelic, Z., additional, Škalko-Basnet, N., additional, Jalšenjak, I., additional, Penacho, N., additional, Pisano, C., additional, Bucci, F., additional, Serafini, S., additional, Martinelli, R., additional, Cupelli, A., additional, Marconi, A., additional, Ferrara, F. F., additional, Santaniello, M., additional, Critelli, L., additional, Tinti, O., additional, Luisi, P., additional, Carminati, P., additional, Galletti, B., additional, Sauer, I., additional, Schleef, M., additional, Voß, C., additional, Schmidt, T., additional, Flaschel, E., additional, König, S., additional, Wenger, T., additional, Dumond, J., additional, Bogetto, N., additional, Reboud-Ravaux, M., additional, Schramm, H. J., additional, Schramm, W., additional, Sheynis, T., additional, Rozner, S., additional, Kolusheva, S., additional, Satchell, D., additional, Jelnik, R., additional, Shigeta, Y., additional, Imanaka, H., additional, Ando, H., additional, Makino, T., additional, Baba, N., additional, Shimizu, K., additional, Takada, M., additional, Baba, K., additional, Namba, Y., additional, Simberg, Dmitri, additional, Danino, Dganit, additional, Talmon, Yeshayahu, additional, Minsky, Abraham, additional, Ferrari, Marilyn E., additional, Wheeler, Carl J., additional, Barenholz, Yechezkel, additional, Takada, Miki, additional, Shimizu, Kosuke, additional, Kuromi, Koici, additional, Takeuchi, Y., additional, North, J. R., additional, Nango, M., additional, Tewes, B., additional, Köchling, T., additional, Deissler, M., additional, Kühl, C., additional, Marx, U., additional, Strote, G., additional, Gropp, F., additional, Qualls, Marquita M., additional, Kim, Jong-Mok, additional, Thompson, David H., additional, Zhang, Zhi-Yi, additional, Shum, Pochi, additional, Collier, Joel H., additional, Hu, Bi-Huang, additional, Ruberti, Jeffrey W., additional, Messersmith, Phillip B., additional, Tsuruda, T., additional, Nakade, A., additional, Sadzuka, Y., additional, Hirota, S., additional, Sonobe, T., additional, Vorauer-Uhl, K., additional, Wagner, A., additional, Katinger, H., additional, Weeke-Klimp, A. H., additional, Bartsch, M., additional, Meijer, D. K. F., additional, Zeisig, R., additional, Walther, W., additional, Reß, A., additional, Fichtner, I., additional, Zschörnig, O., additional, Schiller, J., additional, Süß, M., additional, Bergmeier, C., additional, Arnold, K., additional, Nchinda, Godwin, additional, Überla, Klaus, additional, and Zschörnig, Olaf, additional

Published
2003
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11. Oral Presentations—Abstracts

Author

Bartsch, M., primary, Meijer, D. K. F., additional, Scherphof, G. L., additional, Kamps, J. A. A. M., additional, Erdoğan, S., additional, Özer, A. Y., additional, Caner, B., additional, Bilgili, H., additional, Ickenstein, L. M., additional, Edwards, K., additional, Karlsson, G., additional, Mayer, L. D., additional, Eley, Crispin G. S., additional, Hu, Ning, additional, Jensen, Gerard M., additional, Kawahara, K., additional, Sekiguchi, A., additional, Kiyoki, E., additional, Morimoto, K., additional, Boerman, O. C., additional, Miyajima, M., additional, Kimura, J., additional, Koning, G. A., additional, Morselt, H. W. M., additional, Metselaar, Josbert M., additional, Wauben, Marca H. M., additional, Boerman, Otto C., additional, van Lent, Peter L., additional, Storm, Gert, additional, Pastorino, F., additional, Brignole, C., additional, Marimpietri, D., additional, Moase, E. H., additional, Allen, T. M., additional, Ponzoni, M., additional, Romøren, K., additional, Thu, B. J., additional, Evensen, Ø, additional, Rossi, S., additional, Ristori, S., additional, Martini, G., additional, Schiffelers, R. M., additional, Molema, G., additional, ten Hagen, T. L. M., additional, Janssen, A. P. C. A., additional, Ebben, R. G., additional, Schraa, A. J., additional, Kok, R. J., additional, Koning, G., additional, Storm, G., additional, Simões, S. I., additional, Marques, C. M., additional, Cruz, M. E., additional, Cevc, G., additional, Martins, M. B., additional, Summers, D., additional, Ruff, D., additional, Smalling, R. W., additional, Cardoza, D., additional, Dottavio, D., additional, Lasic, D., additional, Szebeni, J., additional, Baranyi, L., additional, Savay, S., additional, Milosevits, J., additional, Bunger, R., additional, Laverman, P., additional, Metselaar, J. M., additional, Chanan-Khan, A., additional, Liebes, L., additional, Muggia, F. M., additional, Cohen, R., additional, Barenholz, Y., additional, Alving, C. R., additional, Hoving, S., additional, Seynhaeve, A. L. B., additional, van Tiel, S. T., additional, Eggermont, A. M. M., additional, Tokutomi, K., additional, Sadzuka, Y., additional, Igarashi, A., additional, Konno, H., additional, and Sonobe, T., additional

Published
2003
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17. Poster Abstracts

Author

Littger, Ralf, Alke, Alexandra, Tewes, Bernhard, Gropp, Felix, Asai, T., Watanabe, K., Kuromi, K., Kurohane, K., Ogino, K., Taki, T., Tsukada, H., Nakayama, J., Oku, N., Babai, I., Matyas, G., Baranji, L., Milosevits, J., Alving, C. R., Bendas, G., Rothe, U., Scherphof, G. L., Kamps, J. A. A. M., Kessner, S., Rothe, U., Bendas, G., Carafa, M., Di Stefano, A., Sozio, P., Cacciatore, I., Mosciatti, B., Santucci, E., Choice, E., Harvie, P., Galbraith, T., Zunder, E., Dutzar, B., Anklesaria, P., Paul, R., Cocquyt, J., De Cuyper, M., Van der Meeren, P., Cruz, M. E. M., Gaspar, M. M., Silva, M. T., Dathe, M., Nikolenko, H., Wessolowski, A., Schmieder, P., Beyermann, M., Bienert, M., Santos, N. Dos, Cox, K. A., Allen, C., Gallagher, R. C., Ickenstein, L., Mayer, L. D., Bally, M. B., Fischer, S., Margalit, R., Freisleben, H.-J., Garidel, P., Chen, H. C., Moore, D., Mendelsohn, R., Garidel, P., Keller, M., Hildebrand, A., Blume, A., Girão da Cruz, M. T., Simões, S., Pedroso de Lima, M. C., Graser, A., Nahde, T., Fahr, A., Müller, R., Müller-Brüsselbach, S., Harvie, P., Dutzar, B., Choice, E., Cudmore, S., O'Mahony, D., Anklesaria, P., Paul, R., Hoving, S., van Tiel, S. T., Seynhaeve, A. L. B., Ambagtsheer, G., Eggermont, A. M. M., ten Hagen, T. L. M., Høyrup, P., Jensen, S. S., Jørgensen, K., Iden, D., Kuang, H., Mullen, P., Jacobs, C., Roben, P., Stevens, T., Lollo, C., Ishida, T., Maeda, R., Masuda, K., Ichihara, M., Kiwada, H., Jung, K., Reszka, R., Kaiser, N., Ohloff, I., Linser-Haar, S., Massing, U., Schubert, R., Kan, P., Tsao, C. W., Chen, W. K., Wang, A. J., Kimpfler, A., Gerber, C., Wieschollek, A., Bruchelt, G., Schubert, R., Kobayashi, T., Okada, Y., Ishida, T., Sone, S., Harashima, H., Maruyama, K., Kiwada, H., Kondo, Masayo, Lee, Chun Man, Tanaka, Toshiyuki, Su, Wei, Kitagawa, Toru, Ito, Toshinori, Matsuda, Hikaru, Murai, Toshiyuki, Miyasaka, Masayuki, Junji, Kimura, Kondo, Masami, Asai, Tomohiro, Ogino, Koichi, Taki, Takao, Tsukada, Hideo, Baba, Kazuhiko, Oku, Naoto, Koning, G. A., Wauben, M. H. M., ten Hagen, T. L. M., Vestweber, D., Everts, M., Kok, R. J., Schraa, A. J., Molema, G., Schiffelers, R. M., Storm, G., Kristl, J., Šentjurc, M., Abramovi, Z., Landry, S., Perron, S., Bestman-Smith, J., Désormeaux, A., Tremblay, M. J., Bergeron, M. G., Madeira, C., Loura, L. M. S., Fedorov, A., Prieto, M., Aires-Barros, M. R., Marques, C. M., Simões, S. I., Cruz, M. E., Cevc, G., Martins, M. B., Moreira, J. N., Gaspar, R., Allen, T. M., Esposito, C., Ortaggi, G., Bianco, A., Bonadies, F., Malizia, D., Napolitano, R., Cametti, C., Mossa, G., Endert, Gerold, Essler, Frank, Lutz, Silke, Panzner, Steffen, Pastorino, F., Brignole, C., Pagnan, G., Moase, E. H., Allen, T. M., Ponzoni, M., Pavelic, Z., Škalko-Basnet, N., Jalšenjak, I., Penacho, N., Simões, S., Pedroso de Lima, M. C., Pisano, C., Bucci, F., Serafini, S., Martinelli, R., Cupelli, A., Marconi, A., Ferrara, F. F., Santaniello, M., Critelli, L., Tinti, O., Luisi, P., Carminati, P., Santaniello, M., Bucci, F., Tinti, O., Pisano, C., Critelli, L., Galletti, B., Luisi, P., Carminati, P., Sauer, I., Nikolenko, H., Dathe, M., Schleef, M., Voß, C., Schmidt, T., Flaschel, E., König, S., Wenger, T., Dumond, J., Bogetto, N., Reboud-Ravaux, M., Schramm, H. J., Schramm, W., Sheynis, T., Rozner, S., Kolusheva, S., Satchell, D., Jelnik, R., Shigeta, Y., Imanaka, H., Ando, H., Makino, T., Kurohane, K., Oku, N., Baba, N., Shimizu, K., Asai, T., Takada, M., Baba, K., Namba, Y., Oku, N., Simberg, Dmitri, Danino, Dganit, Talmon, Yeshayahu, Minsky, Abraham, Ferrari, Marilyn E., Wheeler, Carl J., Barenholz, Yechezkel, Takada, Miki, Shimizu, Kosuke, Kuromi, Koici, Asai, Tomohiro, Baba, Kazuhiko, Oku, Naoto, Takeuchi, Y., Kurohane, K., North, J. R., Namba, Y., Nango, M., Oku, N., Tewes, B., Köchling, T., Deissler, M., Kühl, C., Marx, U., Strote, G., Gropp, F., Qualls, Marquita M., Kim, Jong-Mok, Thompson, David H., Zhang, Zhi-Yi, Shum, Pochi, Collier, Joel H., Hu, Bi-Huang, Ruberti, Jeffrey W., Messersmith, Phillip B., Thompson, David H., Tsuruda, T., Nakade, A., Sadzuka, Y., Hirota, S., Sonobe, T., Vorauer-Uhl, K., Wagner, A., Katinger, H., Wagner, A., Vorauer-Uhl, K., Katinger, H., Weeke-Klimp, A. H., Bartsch, M., Meijer, D. K. F., Scherphof, G. L., Kamps, J. A. A. M., Zeisig, R., Walther, W., Reß, A., Fichtner, I., Zschörnig, O., Schiller, J., Süß, M., Bergmeier, C., Arnold, K., Nchinda, Godwin, Überla, Klaus, and Zschörnig, Olaf

Abstract

DOCSPER—A Synthetic Lipid Fit for In Vivo ApplicationDOCSPER [1,3-Dioleoyloxy-2-(N5-carbamoyl-spermine)-propane] is a cationic amphiphile consisting of a hydrophobic 1,3 dioleylglycerol moiety and threefold positively charged spermine head group (1). We optimised the 5-step-synthesis of the lipospermine and after up-scaling we have obtained sufficient amounts to initiate preclinical investigations. DOCSPER was tested for its ability to transfect eukaryotic cells in vitro. It has proven to possess high transfection efficiency in comparison to commercially available liposomal transfection agents. Furthermore, DOCSPER was extensively tested in several in vivo studies (23). These studies revealed a high transfection efficiency, whereas very low toxicity levels were detected. Thus, the results clearly indicate that the cationic lipid DOCSPER is a reliable, low-risk system for broad applications in gene therapy.Groth D. et al. Int J Pharm 1998; 162:143–157.Nikol S. et al. Int J Angiol 2000; 9:87–95.Armeanu S. et al. Mol Ther 2000; 1(4):366–375.

Published
1982
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18. Oral Presentations—Abstracts

Author

Bartsch, M., Meijer, D. K. F., Scherphof, G. L., Kamps, J. A. A. M., Erdoan, S., Özer, A. Y., Caner, B., Bilgili, H., Ickenstein, L. M., Edwards, K., Karlsson, G., Mayer, L. D., Eley, Crispin G. S., Hu, Ning, Jensen, Gerard M., Kawahara, K., Sekiguchi, A., Kiyoki, E., Morimoto, K., Boerman, O. C., Miyajima, M., Kimura, J., Koning, G. A., Kimura, J., Morselt, H. W. M., Kamps, J. A. A. M., Scherphof, G. L., Metselaar, Josbert M., Wauben, Marca H. M., Boerman, Otto C., van Lent, Peter L., Storm, Gert, Pastorino, F., Brignole, C., Marimpietri, D., Moase, E. H., Allen, T. M., Ponzoni, M., Romøren, K., Thu, B. J., Evensen, Ø, Rossi, S., Karlsson, G., Ristori, S., Martini, G., Edwards, K., Schiffelers, R. M., Molema, G., Molema, G., ten Hagen, T. L. M., Janssen, A. P. C. A., Ebben, R. G., Schraa, A. J., Kok, R. J., Koning, G., Storm, G., Simões, S. I., Marques, C. M., Cruz, M. E., Cevc, G., Martins, M. B., Summers, D., Ruff, D., Smalling, R. W., Cardoza, D., Dottavio, D., Lasic, D., Szebeni, J., Baranyi, L., Savay, S., Milosevits, J., Bunger, R., Laverman, P., Metselaar, J. M., Storm, G., Chanan-Khan, A., Liebes, L., Muggia, F. M., Cohen, R., Barenholz, Y., Alving, C. R., ten Hagen, T. L. M., Hoving, S., Seynhaeve, A. L. B., van Tiel, S. T., Eggermont, A. M. M., Tokutomi, K., Sadzuka, Y., Igarashi, A., Konno, H., and Sonobe, T.

Abstract

Targeted Delivery of Antisense Oligodeoxynucleotides In Vivo by Means of Coated Cationic LipoplexesEarlier we reported on the massive uptake of liposomes surface-modified with negatively charged aconitylated albumin (Aco-HSA) by liver endothelial cells (EC) in vivo. In the present work we apply this principle for in vivo delivery of antisense oligodeoxynucleotides (ODN) to these cells by means of coated cationic lipoplexes (CCL) (1). CCL were prepared by complexing ODN with the cationic lipid DOTAP and subsequent coating of the complex by neutral lipids including a lipid-anchored poly(ethylene glycol). Aco-HSA was covalently coupled.The Aco-HSA-CCLs were 160 nm in size, contained 1.03 ± 0.35 nmol ODN and 54 ± 18 µg Aco-HSA per µ mol total lipid. The Aco-HSA-CCLs were rapidly eliminated from plasma, 60 of the injected dose being recovered in the liver after 30 m. Within the liver, the EC accounted for two thirds of total liver uptake. Non-targeted CCLs were eliminated very slowly: after 30 m >90 of the particles was in the blood. Currently, we compare the encapsulation efficiency, stability and targetability of the CCL with stabilized antisense lipid particles (SALP) (2), while also the biological activity of these carriers is addressed. In conclusion our results demonstrate that antisense ODN can be targeted very efficiently to EC in vivo, employing plasma-stable CCL, surface modified with negatively charged albumin.ReferencesStuart DD, Allen TM. BBA 2000; 1463:219–229.Semple S. et al. BBA 2001; 1510: 152–166.

Published
1982
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19. Dynamic contrast-enhanced MRI using macromolecular contrast media for monitoring the response to isolated limb perfusion in experimental soft-tissue sarcomas.

Author

Preda A, Wielopolski PA, Ten Hagen TL, van Vliet M, Veenland JF, Ambagtsheer G, van Tiel ST, Vogel MW, Eggermont AM, Krestin GP, and van Dijke CF

Subjects
Animals, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Chemotherapy, Cancer, Regional Perfusion methods, Extremities blood supply, Macromolecular Substances, Male, Prognosis, Rats, Rats, Inbred BN, Treatment Outcome, Albumins, Contrast Media, Gadolinium DTPA, Image Enhancement methods, Magnetic Resonance Imaging methods, Melphalan administration & dosage, Sarcoma, Experimental diagnosis, Sarcoma, Experimental drug therapy, Tumor Necrosis Factor-alpha administration & dosage
Abstract

The objective of this study was to evaluate the potential of dynamic contrast-enhanced MRI for quantitative characterization of tumor microvessels and to assess the microvascular changes in response to isolated limb perfusion with TNF-alpha and melphalan. Dynamic contrast-enhanced MRI was performed in an experimental cancer model, using a macromolecular contrast medium, albumin-(Gd-DTPA)45. Small fragments of BN 175, a soft-tissue sarcoma, were implanted in 11 brown Norway (BN) rats. Animals were assigned randomly to a control (Haemaccel) or drug-treated group (TNF-alpha/melphalan). MRI was performed at baseline and 24 h after ILP. The transendothelial permeability (K(PS)) and the fractional plasma volume (fPV) were estimated from the kinetic analysis of MR data using a two-compartment bi-directional model. K(PS) and fPV decreased significantly in the drug-treated group compared to baseline (p<0.05). In addition, K(PS) post therapy was significantly lower (p<0.05) in the drug-treated group than in the control group. There was no significant difference in fPV between the drug-treated and the control group after therapy. Tumor microvascular changes in response to isolated limb perfusion can be determined after 24 h by dynamic contrast-enhanced MRI. The data obtained in this experimental model suggest possible applications in the clinical setting, using the appropriate MR contrast agents.

Published
2004
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20. Lack of efficacy of Doxil in TNF-alpha-based isolated limb perfusion in sarcoma-bearing rats.

Author

ten Hagen TL, Hoving S, Ambagtsheer G, van Tiel ST, and Eggermont AM

Subjects
Animals, Disease Models, Animal, Hindlimb drug effects, Hindlimb pathology, Humans, Male, Organ Culture Techniques, Rats, Antibiotics, Antineoplastic pharmacology, Chemotherapy, Cancer, Regional Perfusion, Doxorubicin pharmacology, Sarcoma drug therapy, Tumor Necrosis Factor-alpha pharmacology
Abstract

Here we show that Doxil has minimal antitumour activity in the isolated limb perfusion (ILP) setting and its activity was not enhanced by the addition of tumour necrosis factor (TNF). Doxil accumulation in tumour tissue was low and also not augmented by TNF. In contrast, activity of free conventional doxorubicin was enhanced by TNF. We conclude that application of Doxil in a TNF-based ILP is not a useful alternative to free conventional doxorubicin or melphalan.

Published
2004
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21. Degree of tumour vascularity correlates with drug accumulation and tumour response upon TNF-alpha-based isolated hepatic perfusion.

Author

van Etten B, de Vries MR, van IJken MG, Lans TE, Guetens G, Ambagtsheer G, van Tiel ST, de Boeck G, de Bruijn EA, Eggermont AM, and ten Hagen TL

Subjects
Animals, Cell Division drug effects, Chemotherapy, Cancer, Regional Perfusion methods, Colonic Neoplasms blood supply, Colonic Neoplasms metabolism, Disease Models, Animal, Immunoenzyme Techniques, In Vitro Techniques, Liver Neoplasms, Experimental secondary, Male, Microcirculation, Osteosarcoma blood supply, Osteosarcoma metabolism, Rats, Rats, Inbred BN, Sarcoma blood supply, Sarcoma metabolism, Tissue Distribution, Antineoplastic Agents administration & dosage, Antineoplastic Agents, Alkylating pharmacokinetics, Liver Neoplasms, Experimental blood supply, Liver Neoplasms, Experimental metabolism, Melphalan pharmacokinetics, Tumor Necrosis Factor-alpha administration & dosage
Abstract

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-alpha) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-alpha in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-alpha contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastases model we studied three different tumours: colon carcinoma CC531, ROS-1 osteosarcoma and BN-175 soft-tissue sarcoma which exhibit different degrees of vascularisation. IHP was performed with melphalan with or without the addition of TNF-alpha. IHP with melphalan alone resulted, in all tumour types, in a decreased growth rate. However in the BN-175 tumour addition of TNF-alpha resulted in a strong synergistic effect. In the majority of the BN-175 tumour-bearing rats, a complete response was achieved. In vitro cytoxicity studies showed no sensitivity (CC531 and BN-175) or only minor sensitivity (ROS-1) to TNF-alpha, ruling out a direct interaction of TNF-alpha with tumour cells. The response rate in BN-175 tumour-bearing rats when TNF-alpha was coadministrated with melphalan was strongly correlated with drug accumulation in tumour tissue, as only in these rats a five-fold increased melphalan concentration was observed. Secondly, immunohistochemical analysis of microvascular density (MVD) of the tumour showed a significantly higher MVD for BN-175 tumour compared to CC531 and ROS-1. These results indicate a direct relation between vascularity of the tumour and TNF-alpha mediated effects. Assessment of the tumour vasculature of liver metastases would be a way of establishing an indication for the utility of TNF-alpha in this setting.

Published
2003
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22. Adenovirus-mediated interleukin 3 beta gene transfer by isolated limb perfusion inhibits growth of limb sarcoma in rats.

Author

de Wilt JH, Bout A, Eggermont AM, van Tiel ST, de Vries MW, ten Hagen TL, de Roos WK, Valerio D, and van der Kaaden ME

Subjects
Animals, Dose-Response Relationship, Drug, Histamine blood, Leukocytes metabolism, Male, Melphalan therapeutic use, Neoplasm Transplantation, Osteosarcoma therapy, Perfusion, Promoter Regions, Genetic, Rats, Sarcoma therapy, Time Factors, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha therapeutic use, Adenoviridae genetics, Carrier Proteins genetics, Extremities growth & development, Extremities physiology, Gene Transfer Techniques, Receptors, Interleukin-3
Abstract

Cytokine gene transfer using (multiple) intratumoral injections can induce tumor regression in several animal models, but this administration technique limits the use for human gene therapy. In the present studies we describe tumor growth inhibition of established limb sarcomas after a single isolated limb perfusion (ILP) with recombinant adenoviral vectors harboring the rat IL-3 beta gene (IG.Ad.CMV.rIL-3 beta). In contrast, a single intratumoral injection or intravenous administration did not affect tumor growth. Dose-finding studies demonstrated a dose-dependent response with a loss of antitumor effect below 1 x 10(9) IU of IG.Ad.CMV.rIL-3 beta. Perfusions with adenoviral vectors bearing a weaker promoter (MLP promoter) driving the rIL-3 beta gene did not result in antitumor responses, suggesting that the rIL-3 beta-mediated antitumor effect depends on the amount of rIL-3 beta protein expressed by the infected cells. Furthermore, it was shown by direct comparison that ILP with IG.Ad.CMV.rIL-3 beta in the ROS-1 osteosarcoma model is at least as efficient as the established therapy with the combination of TNF-alpha and melphalan. Treatment with IG.Ad.CMV.rIL-3 beta induced a transient dose-dependent leukocytosis accompanied by an increase in peripheral blood levels of histamine. Leukocyte infiltrations were also histopathologically demonstrated in tumors after perfusion. These results demonstrate that ILP with recombinant adenoviral vectors carrying the IL-3 beta transgene inhibits tumor growth in rats and suggest that cytokine gene therapy using this administration technique might be beneficial for clinical cancer treatment.

Published
2001
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23. Low-dose tumor necrosis factor-alpha augments antitumor activity of stealth liposomal doxorubicin (DOXIL) in soft tissue sarcoma-bearing rats.

Author

Ten Hagen TL, Van Der Veen AH, Nooijen PT, Van Tiel ST, Seynhaeve AL, and Eggermont AM

Subjects
Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Doxorubicin administration & dosage, Doxorubicin pharmacokinetics, Drug Carriers, Drug Screening Assays, Antitumor, Drug Synergism, Liposomes, Male, Rats, Sarcoma metabolism, Tissue Distribution, Tumor Necrosis Factor-alpha administration & dosage, Antineoplastic Agents pharmacology, Doxorubicin pharmacology, Sarcoma drug therapy, Tumor Necrosis Factor-alpha pharmacology
Abstract

It has previously been demonstrated in the setting of an isolated limb perfusion that application of high-dose TNF-alpha in combination with chemotherapy (melphalan, doxorubicin) results in strong synergistic antitumor effects in both the clinical and preclinical settings. In this study, we demonstrate that systemic administration of low-dose TNF-alpha augments the antitumor activity of a liposomal formulation of doxorubicin (DOXIL(R)). Addition of TNF-alpha to a DOXIL(R) regimen, which by itself induced some tumor growth delay, resulted in massive necrosis and regression of tumors. Furthermore, we could demonstrate a significant increase of liposomal drug in the tumor tissue when TNF-alpha had been co-administered. Administration of TNF-alpha augmented DOXIL(R) accumulation only after repeated injections, whereas accumulation of free doxorubicin was not affected by TNF-alpha. Drug levels in the tumor interstitium appeared crucial as intracellular levels of free or liposome-associated doxorubicin were not increased by TNF-alpha. Therefore, we hypothesize that low-dose TNF-alpha augments leakage of liposomal drug into the tumor interstitium, explaining the observed improved antitumor effects. Regarding the effects of systemic administration of low doses of TNF-alpha, these findings may be important for enhanced tumor targeting of various liposomal drug formulations., (Copyright 2000 Wiley-Liss, Inc.)

Published
2000
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24. Tumor necrosis factor-alpha augments tumor effects in isolated hepatic perfusion with melphalan in a rat sarcoma model.

Author

van Ijken MG, van Etten B, de Wilt JH, van Tiel ST, ten Hagen TL, and Eggermont AM

Subjects
Adjuvants, Immunologic administration & dosage, Animals, Antineoplastic Agents, Alkylating therapeutic use, Combined Modality Therapy, Liver blood supply, Male, Rats, Tumor Necrosis Factor-alpha analysis, Chemotherapy, Cancer, Regional Perfusion methods, Liver Neoplasms drug therapy, Liver Neoplasms therapy, Melphalan therapeutic use, Sarcoma, Experimental drug therapy, Sarcoma, Experimental therapy, Tumor Necrosis Factor-alpha administration & dosage
Abstract

Isolated hepatic perfusion (IHP) is an attractive approach to treating nonresectable liver tumors, because the effects of systemic chemotherapy are poor and its application is hampered by severe general toxicity. In clinical and experimental settings, the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF alpha) in combination with melphalan to treat melanoma in transit and soft-tissue sarcoma has been well established. In an ILP model in rats, the authors previously observed synergistic anti-tumor effects of TNF and melphalan on BN 175 soft-tissue sarcoma extremity tumors. The aim of the current study was to determine whether similar synergy in anti-tumor effects could be achieved by treating experimental BN 175 soft-tissue sarcoma liver tumors by IHP using these agents. The authors found that IHP with TNF and melphalan resulted in a dramatic increase in regional concentrations of perfused agents with virtually no concomitant systemic leakage. Isolated hepatic perfusion with only carrier solution resulted in a significantly diminished growth rate of BN 175 liver tumors compared with the growth rate of tumors in nonperfused rats. Perfusion with melphalan alone resulted in minimal anti-tumor effects. Perfusion with only TNF had a slight growth-stimulatory effect on the BN 175 liver tumors, but no negative effects on tumor growth were observed. When TNF was added to melphalan, a dramatic anti-tumor effect was observed. Thus, as in the rat ILP setting, the anti-tumor effect is augmented when TNF is added to IHP with melphalan to treat BN 175 soft-tissue sarcoma tumor-bearing rats. Strikingly, the tumor response was potentiated at relatively low concentrations of TNF compared with concentrations that elicited synergy with melphalan in ILP.

Published
2000
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25. TNF-alpha augments intratumoural concentrations of doxorubicin in TNF-alpha-based isolated limb perfusion in rat sarcoma models and enhances anti-tumour effects.

Author

van der Veen AH, de Wilt JH, Eggermont AM, van Tiel ST, Seynhaeve AL, and ten Hagen TL

Subjects
Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Chemotherapy, Cancer, Regional Perfusion, Doxorubicin therapeutic use, Male, Rats, Sarcoma, Experimental drug therapy, Tumor Necrosis Factor-alpha administration & dosage, Tumor Necrosis Factor-alpha therapeutic use, Antineoplastic Agents pharmacology, Doxorubicin pharmacokinetics, Sarcoma, Experimental metabolism, Tumor Necrosis Factor-alpha pharmacology
Abstract

We have shown previously that isolated limb perfusion (ILP) in sarcoma-bearing rats results in high response rates when melphalan is used in combination with tumour necrosis factor alpha (TNF-alpha). This is in line with observations in patients. Here we show that ILP with doxorubicin in combination with TNF-alpha has comparable effects in two different rat sarcoma tumour models. The addition of TNF-alpha exhibits a synergistic anti-tumour effect, resulting in regression of the tumour in 54% and 100% of the cases for the BN175-fibrosarcoma and the ROS-1 osteosarcoma respectively. The combination is shown to be mandatory for optimal tumour response. The effect of high dose TNF-alpha on the activity of cytotoxic agents in ILP is still unclear. We investigated possible modes by which TNF-alpha could modulate the activity of doxorubicin. In both tumour models increased accumulation of doxorubicin in tumour tissue was found: 3.1-fold in the BN175 and 1.8-fold in the ROS-1 sarcoma after ILP with doxorubicin combined with TNF-alpha in comparison with an ILP with doxorubicin alone. This increase in local drug concentration may explain the synergistic anti-tumour responses after ILP with the combination. In vitro TNF-alpha fails to augment drug uptake in tumour cells or to increase cytotoxicity of the drug. These findings make it unlikely that TNF-alpha directly modulates the activity of doxorubicin in vivo. As TNF-alpha by itself has no or only minimal effect on tumour growth, an increase in local concentrations of chemotherapeutic drugs might well be the main mechanism for the synergistic anti-tumour effects.

Published
2000
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26. Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats.

Author

de Wilt JH, Manusama ER, van Tiel ST, van Ijken MG, ten Hagen TL, and Eggermont AM

Subjects
Animals, Drug Synergism, Hindlimb, Hypoxia, Male, Rats, Rats, Inbred BN, Temperature, Antineoplastic Agents, Alkylating pharmacology, Chemotherapy, Cancer, Regional Perfusion, Melphalan pharmacology, Tumor Necrosis Factor-alpha pharmacology
Abstract

An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 microg TNF and 40 microg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26 degrees C, anti-tumour effects were lost, whereas temperatures of 38-39 degrees C or 42-43 degrees C resulted in higher response rates. However, at 42-43 degrees C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 microg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38 degrees C was mandatory. Moreover, the dose of TNF could be lowered to 10 microg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings.

Published
1999
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