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2. Community participation and multidimensional child growth: evidence from the Vietnam Young Lives study

Author

Gonzalez Martinez, R., Wells, J., Anand, P., Bergeron, G., Pelto, G., Dhansay, A., Haisma, H., and Urban and Regional Studies Institute

Subjects
Nutrition and Dietetics, Medicine (miscellaneous), Food Science
Abstract

Background: Community participation has the potential to improve the effects of interventions and reduce inequalities in child growth. Multidimensional indicators capture such effects and inequalities.\ud \ud Objective: The objective of this study was to measure the association between multidimensional child growth and community participation in two nutrition-sensitive interventions.\ud \ud Methods: A multidimensional index of child growth (MICG) was calculated with the 5-years-old cohort of the Vietnam Young Lives survey. Young Lives is a unique dataset that has information on community participation in the design and implementation stages of two interventions: a health and a WASH intervention. Community participation during the interventions was recorded retrospectively with interviews at household level. Ordinary least squares and quantile regressions were estimated using data of 240 children. A multidimensional index of child advantage (MICA), sex, and location (urban/rural) were included as control covariates. \ud \ud Results: A positive association (post-hoc statistical power = 0.859) was estimated for community participation during the design stage of the WASH intervention, particularly for the most deprived children (p-value < 0.05). Negative effects were estimated for the health intervention during the design stage (p-value < 0.05) and no significant effects were found for community participation during the implementation stage of the interventions. Instead of the physical dimension, the significant associations in the design stage were related to the non-physical dimension of child growth. Inequalities in multidimensional growth were found for children living in rural areas, but not for female children.\ud \ud Conclusions: The association between community participation and multi-dimensional child growth is indicative of the importance of community participation during the design phase of interventions, in particular for the non-physical dimensions of child growth related to social and psychological factors. The benefits of participation were greater for urban children compared to rural children, which deserves further attention.

Published
2022

22. Abstracts of papers and posters

Author

Anthonio, R. L., Willemsen, A. T. M., Visser, T., van Waarde, A., Elzinga, P., Weemaes, A., Meeder, J. G., Pruim, J., Visser, G., Blanksma, P. K., Vaalburg, W., Bloemen, P. G. M., Henricks, P. A. J., van Bloois, L., van den Tweel, M. C., Nijkamp, F. P., Crommelin, D. J. A., Storm, G., de Boer, A. H., Winter, H. M. I., Lerk, C. F., de Boer, J., Meurs, H., Bottone, A. E., Koopal, M., Visser, J. C., Zaagsma, J., Borger P., Kauffman H. F., Vijgen J. L. J., Postma D. S., Vellenga E., Buckley, Theresa L., Buikema, H., van Gilst, W. H., van Veldhuisen, D. J., de Smet, B. J. G. L., Scholtens, E., Lie, K. I., Wesseling, H., Cheung, P. K., Dijkhuis, F. W. D., Bakker, W. W., Visser, J., Coopes, R. P., Benthem, L., van der Leest, J., Roffel, A. F., Coppes, R. P., Zeilstra, L. J. W., Vissink, A., Konings, A. W. T., Dijkstra, M., Veld, G. In't, Müller, M., van den Berg, G. J., Kuipers, F., Vonk, R. J., Elsinga, P. H., Franssen, E. J. F., van der Graaf, W. T. A., de Vries, E. G. E., Visser, G. M., Vos, M. G., Braker, A. H., Visser, T. J., Visser, G. M., Engels, F., van Houwelingen, A. H., van de Velde, M. J., Gansevoort, R. T., Sluiter, W. J., Hemmelder, M. H., de Zeeuw, D., de Jong, P. E., Gelissen, H. P. M. M., Henning, R. H., Epema, A. H., van Eekeren, J., Hennis, P. J., Den Hertog, A., de Graaf, S. S. N., Kellie, S. J., Bloemhof, H., Johnston, I., Besser, M., Chaseling, R. W., Ouvrier, R. A., Uqes, D. R. A., De Haan, A., Geerligs, H. J., Huchshorn, J. P., Van Scharenburg, G. J. M., Wilschut, J., Haas, M., Kluppel, C. A., Meijer, D. K. F., Moolenaar, F., Heerdink, Eibert R., Leufkens, Hubert G., Herings, Ron M. C., Stricker, Bruno H. Ch., Bakker, Albert, Heesen W. F., Beltman F. W., Smit A. J., May J. F., Meyboom-de Jong B., Duin, M., van den Akker, J., te Pas, M. F. W., van Popta, J. P., Nelemans, S. A., van der Linde, H. J., de Boer, A., Sturmans, F., Hessel, E. M., Van Oosterhout, A. J. M., Hofstra, C. L., Garssen, J., van Loveren, H., Savelkoul, H. F. J., Hoekstra, Y., Weersink, E. J. M., de Jong, J. W., van der Belt-Gritter, B., Jonkman, Lisa M., Kemner, Chantal, Koelega, Harry S., van Engeland, Herman, Verbaten, Marinus N., Kalivianakis, M., Zijlstra, I., Verkade, H. J., Elzinga, H., Stellaard, F., Kamps, J. A. A. M., Swart, P. J., Morselt, H., Scherphof, G. L., Kenemans, J. L., Lorist, M. M., Koopen, N. R., Kraneveld, A. D., Koster, A. Si., Kuipers, M. E., Groenink, M., Huisman, H., Schuitemaker, H., Lau, H. S., van den Broek, I. J. P. M., van Dijk, A., Oostinga, J., Porsius, A. J., Lin, Y., Havinga, R., Meijer, R. J., van der Mark, Th. W., Koëter, G. H., Michels, A. A., Nguyen, V. -T., Bensaude, O., Kampinga, H. H., Mohede, Inge C. M., Van Antoon J. M., Molema, Grietje, Edgington, Thomas S., Thorpe, Philip E., Olinga, P., Sandker, G. W., Slooff, M. J. H., Merema, M. T., Groothuis, G. M. M., Hofman, G., Van Ark, I., Paulussen, J. J. C., Fischer, M. J. E., de Mol, N. J., Janssen, L. H. M., Peters, E. Th. J., van der Werf, G. Th., Haaijer-Ruskamp, F. M., Pinto, Yigal M., Rooks, Gerrit, Grandjean, Jean G., Ebels, Tjark, Schunkert, H., Redegeld, Frank A., Garssen, Johan, van Loveren, Henk, Rigter, Irma M., van Groningen, Muck, Boks, Gertjan J., Tollenaere, Jan P., Trollope, Keith I., Vinter, Jeremy G., Hashjin, Gudarz Sadeghi, Folkerts, Gert, van de Loo, Peet G. F., Santing, R. E., Olymulder, C. G., van der Molen, K., Pasman, Y., Scheerens, Heleen, Van Loveren, Henk, Seppenwoolde-Waasdorp, T. J. A., de Boer, P., Van Engelen, H. M. J., Thijssen, J. H. H., Maes, R. A. A., Smit, J., Smit, J. W., Steen, H., Steurs, M. H., Kuks, P. F. M., Leusink, J. A., Szabó, Balázs M., Crijns, Harry J. G. M., Wiesfeld, Ans C. P., Talsma, H., Borchert, J. C. H., van Steenbergen, M. J., Hennink, W. E., Teeuw, K. B., Cromheecke, H., Schreudering, A., Teisman, B. C. H., Maselbas, W., Wolters-Keulemans, G. T. P., Tieleman, R. G., de Langen, C. D. J., Bel, K., Crijns, H. J. G. M., Grandjean, J., Wijffels, M., Klimp, A. H., van de Meer, P. F., Allessie, M. A., van Patot, H. A. Tissot, de Jongh, B. M., Tuininga, Y. S., Brouwer, J., Haaksma, J., Man in't Veld, A. J., Blomjous, F. J., Vingerhoeds, M. H., Belliot, S. O., Haisma, H. J., Visscher, C. A., Huisman, R. M., Navis, G. J., de Vlieger, J. F., van den Wijngaard, P., Wilting, J., van Heuven-Nolsen, D., Voors, A. A., van Brussel, B. L., Plokker, H. W. M., Van Waardenburg R. C. A. M., Meijer, Prins J., De Vries, C., Mulder N. H., Wierenga, P. K., Wilschut J., Schoen P., and Bron R.

Published
1994
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24. Abstracts of papers and posters Meeting on Pharmaceutical Sciences

Author

Coile, Jr., Russell C., Wiedhaup, K., van Bommel, Ilva, Mol, Miriam, de Vries, Michiel, Massey, E. W., Biller, J., Davis, J. N., Adams, H. P., Marler, J. R., Magnani, H. N., Schotte, A., Janssen, P. F. M., Leysen, J. E., Skrabanja, A. T. P., Flendrig, L., van Iren, F., Schrijnemakers, E. W. M., Reinhoud, P. J., Kijne, J. W., Knevelman, A., de Wit, H. J. C., de Vries, J. D., Bult, A., Beijnen, J. H., van Winden, E. C. A., Talsma, H., Crommelin, D. J. A., Storm, G., Oussoren, C., Zuidema, J., Vingerhoeds, M. H., Smit, R. H. P., Dinther, F. v., Hultermans, T., Beumer, T., Fransz, A. N., Vromans, H., Bloemhof, D. A., van Mansvelt, F. J. W., Brouwers, J. R. B. J., Raemaekers, J., Boskma, R. J., Bloemhof, H., de Graaf, S. S. N., Uges, D. R. A., Kosterink, J. G. W., de Jonge, M. W. A., Smit, E. F., Kengen, R. A. M., de Leij, L., Piers, D. A., Shochat, D., The, T. H., Luurtsema, Gert, Franssen, Eric, Visser, Geb, Jeronimus-Stratingh, Margot, Bruins, Andries, Vaalburg, Wim, Luurtsema, G., Medema, J., Elsinga, P. H., Franssen, E. J. F., Visser, G. M., Vaalburg, W., Jmker, Jan I., Uges, Donald R. A., van der Paauw, Hugo, Maas, Max, de Vos, Henk, Hettelaar, Jenny, Slolk, L. M. L., van den Brand, W., Smit, B. J., Franssen, R. M. E., Vinks, A. A. T. M. M., Touw, D. J., Heijerman, H. G. M., Danhof, M., Bakker, W., Hermans, J., Driessen G. J., Wolters R., Go I. H., Fennis J., Gribnau F. W. J., Heerdink, Eibert R., Leufkens, Hubert G., Bakker, Albert, Heerdink, E. R., Lau, H. S., Bakker, A., Porsius, A. J., Beuning, K. S., Postma-Lim, E., de Boer, A., Nagtegaal, J. E., Stecher, N., Sturkenboom, M. C. J. M., de Jong-van den Berg, L. T. W., Cornel, M. C., Stricker, B. H. Ch., Wesseling, H., van den Bemt, P. M. L. A., Kil, P. J. M., Meyboom, R. H. B., de Koning, G. H. P., Herings, Ron M. C., Stricker, Bruno H. Ch., Leufkens, Hubert G. M., Urquhart, John, de Boer, Anthonius, Sturmans, Ferd, Middeibeek, Alma, Sturkenboom, Miriam C. J. M., de Jong-van den Berg, Lolkje T. W., Lammers, M. W., Hekster, Y. A., Keyser, A., Meinardi, H., Renier, W. O., Van Lier, H., Veehof, L., Stewart, R., Mevboom-de Jong, B., Haaijer-Ruskamp, F. M., Visser, L. E., van der Velden, J., Paes, A. H. P., van Mil, J. W. F., Tromp, Th. F. J., Casparie, M. K., Kuijpers, A., Stuvt, P. M. J., Dijkers, F. W., vd Ree, C. M., Ruben, B. A., Mokkink, H. G. A., Post, D., Gubbels, J. W., Stokx, L. J., Foets, M., Florax, C., van Dijk, A., Peters, E. T. J., van der Werf, G. T., Denig, P., Boerkamp, Ellis J. C., Haaijer-Ruskamp, Flora M., Reuyl, Jan C., Versluis, Albert, van Trigtv, Anke M., de Jong- vd Berg, Lolkie T. W., Willems, Jaap, Kaldeway, Hans, Wieringa, Nicolien, Herxheimer, Andrew, Vos, Rein, Heijman, Jennifer, Rikken, Floor, Omta S. W. F., Bouter L. M., van Engelen J. M. L., Leufkens, H. G. M., Steffens, B., Thijssen, J. J. H., de Boer, D., Tissot van Patot, H. A., Leusink, J. A., de Jongh, B. M., Reuvers, Inge H., van der Galiën, Trea A., Tromp, Dick F. J., Hendrikx, N. E. H. W., van der Werf, G. Th., Vos, R., Swart, J. A. A., Haisma, H. J., Borchert, J. C. H., Versantvoort, M. W., van Steenbergen, M. J., Hennink, W. E., Wolthuis, W. N. E., van Hooff, R. J. M., Wientjes, K. J. C., Schmidt, F. J., Schoonen, A. J. M., Te Wierik, G. H. P., Eissens, A. C., Lerk, C. F., Haas, M., Iwema Bakker, W. I., Reinhoudt, D. N., Mijer, D. K. F., de Zeeuw, D., Proost, J. H., Wierda, J. M. K. H., Meijer, D. K. F., Kuipers, M., Swart, P. J., Hendriks, M. M. W. B., Kamps, J. A. A. M., Struska, B., Thomas, C., Nijenhuis, A. M., Scherphof, G. L., Swaan, Peter W., Stehouwer, Marco C., Blok, Eric J. C., Tukker, Josef J., van Dijk, J., Gorissen, H. R. M., Groot-Padberg, Y. M., Olling M., van Gelderen C. E. M., Salomons P., Barends D. M., Meulenbelt J., Rauws A. G., Craane-van Hinsberg, W. H. M., Verhoef, J. C., Junginger, H., and Boddé, H. E.

Published
1993
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28. 'It is the medicines that keep us alive'

Author

Metta, E. (Emmy), Haisma, H. (Hinke), Kessy, F. (Flora), Geubbels, E. (Eveline), Hutter, I. (Inge), Bailey, A. (Ajay), Metta, E. (Emmy), Haisma, H. (Hinke), Kessy, F. (Flora), Geubbels, E. (Eveline), Hutter, I. (Inge), and Bailey, A. (Ajay)

Abstract

Background: Diabetes is a chronic condition which requires many patients to use medications for the remainder of their lives. While this regimen is demanding, little research has been done on the experiences individuals have with diabetes medication use and the continuity of use, especially patients from rural areas of Tanzania. This study explores the lived experiences of diabetes medication use and the continuity of use among adult diabetes patients from rural communities with limited access to diabetes medicines. Methods: We conducted 19 in-depth interviews to explore patients’ experiences with diabetes medication use and the continuity of use. We employed the 5As of access to care to situate the behavioral practices surrounding diabetes medication use in the study settings. The data analysis followed grounded theory principles, and was conducted with the help of NVivo 9. Results: Study participants expressed positive attitudes toward the use of diabetes medicines, but also concerns about affordability. The patients employed two main strategies for dealing with the cost. The first was to increase their available funds by spending less money on family needs, selling household property, asking family and friends for money, or borrowing cash. They also reported sourcing medicines from pharmacies to save on consultation and laboratory costs. Second, participants reported using less than the recommended dosage or skipping doses, and sharing medicines. The geographic accessibility of diabetes service providers, the availability of medication, and the organization of the diabetes services were also cited as barriers to taking medications and to using them continuously. Conclusions: The strategies employed by the people in this study illustrate their resilience in the face of poverty and failing health care systems. More comprehensive strategies are therefore needed to encourage consistent medication use among people with chronic conditions. These strategies could includ

Published
2015
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29. 'In a situation of rescuing life'

Author

Metta, E. (Emmy), Bailey, A. (Ajay), Kessy, F. (Flora), Geubbels, E. (Eveline), Hutter, I. (Inge), Haisma, H. (Hinke), Metta, E. (Emmy), Bailey, A. (Ajay), Kessy, F. (Flora), Geubbels, E. (Eveline), Hutter, I. (Inge), and Haisma, H. (Hinke)

Abstract

Background: Diabetes mellitus is an emerging public health problem in Tanzania. For the community and the health system to respond adequately to this problem, it is important that we understand the meanings given to its symptoms, and the care-seeking practices of individuals. Methods: To explore collective views on the meanings given to diabetes symptoms, we conducted nine focus group discussions with adult diabetes patients and members of the general community. To gain a better understanding of how the meanings in the community inform the care-seeking practices of individuals, 19 in-depth interviews were conducted with diabetes patients. The data were analyzed using principles of grounded theory and applying cultural schema theory as a deductive framework. Results: In the communities and among the patients, knowledge and awareness of diabetes are limited. Both people with diabetes and community members referred to their prevailing cultural meaning systems and schemas for infectious diseases to interpret and assign meaning to the emerging symptoms. Diabetes patients reported that they had initially used anti-malarial medicines because they believed their symptoms—like headache, fever, and tiredness—were suggestive of malaria. Schemas for body image informed the meaning given to diabetes symptoms similar to those of HIV, like severe weight loss. Confusion among members of the community about the diabetes symptoms instigated tension, causing patients to be mistrusted and stigmatized. The process of meaning-giving and the diagnosis of the diabetes symptoms was challenging for both patients and health care professionals. Diabetes patients reported being initially misdiagnosed and treated for other conditions by medical professionals. The inability to assign meaning to the symptoms and determine their etiologies informed the decision made by some patients to consult traditional healers, and to associate their symptoms with witchcraft causes. Conclusion: The meanings give

Published
2015
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34. Secretion of thymidine kinase to increase the effectivity of suicide gene therapy results in the loss of enzymatic activity

Author

Beerens, A. M. J., Rots, M. G., Bermudez, B., De Vries, E. F. J., Haisma, H. J., Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Biopharmaceuticals, Discovery, Design and Delivery (BDDD)

Subjects
FUSION PROTEIN, TUMOR-CELLS, enzymatic activity, cancer gene therapy, IN-VITRO, CANCER, suicide gene therapy, FIBER KNOB, INTERCELLULAR TRAFFICKING, thymidine kinase, ER EXPORT, VP22, ADENOVIRAL VECTOR, GLUCURONIDE PRODRUG
Abstract

Low efficiency of gene transfer is one of the major limitations of gene therapy. A solution to this problem may be transmission; by modification of the transgene, the gene product can be secreted and internalized by the surrounding cells. Cancer gene therapy using the herpes simplex thymidine kinase (HSV-TK) suicide gene is a promising treatment, and TK has been used in clinical trials with some success. However, this kind of therapy has limited efficacy due to the low level of gene transfer reached. A modified TK protein, capable of migrating from the producing cell to neighboring cells, would result in a greater proportion of cells affected by the treatment. As a first step towards transmission, we constructed a secretory form of HSV-TK by including the Ig leader peptide in the gene. An endoplasmatic reticulum export signal was added to the construct to further improve its secretion. Secretion and protein production in cancer cells, the enzymatic activity of the modified proteins and the ability of the modified TK to sensitize cancer cells to ganciclovir were tested. Addition of the Ig leader resulted in high levels of secretion of HSV-TK, with up to 70% of the total amount of protein secreted. Inclusion of an ER export signal did not further improve secretion. The enzyme activity of the secreted TK however, was decreased when compared to native TK. This study is the first to report on secretion of TK, and provides a first step in a novel strategy to improve the efficiency of cancer gene therapy. The loss of function in secreted TK however, may present a major hurdle in the development of a transmitted form of TK.

Published
2008

35. Fusion of herpes simplex virus thymidine kinase to VP22 does not result in intercellular trafficking of the protein

Author

Beerens, A. M. J., Rots, M. G., de Vries, E. F. J., Haisma, H. J., Damage and Repair in Cancer Development and Cancer Treatment (DARE), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Biopharmaceuticals, Discovery, Design and Delivery (BDDD)

Subjects
TAT PROTEIN, HUMAN-MALIGNANT GLIOMA, intercellular trafficking, SUICIDE GENE-THERAPY, TUMOR-CELLS, HUMAN IMMUNODEFICIENCY VIRUS, protein transduction domain, TRANSDUCTION, suicide gene therapy, HSV-TK, PROSTATE-CANCER, VP22 tegument protein, DELIVERY, MEMBRANE TRANSLOCATION, fusion protein, IN-VIVO
Abstract

Suicide gene therapy is a promising approach for the treatment of cancer. Current protocols, however, suffer from low efficiency. We tried to alleviate this problem by developing a transgene that will spread from the initially transduced cell to the surrounding cells (transmission). We used herpes simplex virus (HSV) VP22 as a signal for cellular uptake of HSV-1 thymidine kinase (TK). By co-culturing naive cells with cells producing a TK-VP22 fusion protein, we detected intercellular trafficking of this protein. We used a variety of techniques, including two-color flow cytometry and cytotoxicity assays to detect the presence of TK in the non-producing cells. We confirmed intercellular migration of VP22. We did not detect any intercellular trafficking of the TK-VP22 fusion protein, by various fixation methods or flow cytometry. In ganciclovir sensitivity assays, we found no difference between the efficiency of TK (IC50=3.15 +/- 0.76 mu g/ml) and TK-VP22 (IC50=2.27 +/- 0.59 mu g/ml). Using a cell-free enzyme activity assay we showed that fusion of TK to VP22 did not change the enzyme activity. In conclusion, we described novel and robust methods to detect intercellular trafficking. From our data we concluded that protein transmission of TK by VP22 for gene therapy is not likely to be successful. In addition, we described a useful and quantifiable assay to measure the enzymatic activity of TK and TK fusion proteins, and described some common properties of VP22 fusion proteins that may explain the different results that have been obtained by others.

Published
2007

36. Abstracts of papers

Author

Meijer, D. K. F., Crommelin, D. J. A., Hoes, C. J. T., van Heeswijk, W. A. R., de Grooth, B., Mud, J., Greve, J., Feljen, J., Goedemans, W. Th., de Jong, M. M. Th., Haisma, H., Hilkens, J., Roerdink, F. H., Spanjer, H. H., Derksen, J. T. P., Daemen, C. A. H. H., Bakker, I. A. J. M., Scherphof, G. L., Driessen, O. M. J., Burger, J. J., McVie, J. G., Fokkens, J. G., Bootsma, H. P. R., Neutel, J. W., van der Sluijs, P., Moolenaar, F., Storm, G., Steerenberg, P. A., van Gessel, H., and Roerdink, F.

Published
1985
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37. The protective mechanism of tauroursodeoxycholic acid against bile acid induced apoptosis

Author

Schoemaker, M, Gommans, W, Homan, M, Liston, P, Trautwein, C, van Goor, H, Poelstra, K, Haisma, H, Jansen, P, Moshage, H, Faculteit Medische Wetenschappen/UMCG, University of Groningen, Nanotechnology and Biophysics in Medicine (NANOBIOMED), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)

Published
2002

38. Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer

Author

van der Poel, H G, Molenaar, Bonnie, van Beusechem, V W, Haisma, H J, Rodriguez, R, Curiel, D T, Gerritsen, W R, Medical oncology laboratory, and CCA - Cancer biology and immunology

Abstract

PURPOSE: We evaluated the delivery and oncolytic potential of targeted replication competent adenoviruses in bladder cancer lines. MATERIALS AND METHODS: Seven established human bladder cancer tumor lines (5637, SW800, TCCsup, J82, Scaber, T24 and 253J) were studied for the expression of integrins alpha(v)beta3, alpha(v)beta5, Coxsackievirus and adenovirus receptor, epidermal growth factor receptor (EGF-R) and epithelial cell adhesion molecule antigens using flow cytometry analysis. Bispecific single chain Fv fragments were used to target replication deficient luciferase reporter adenovirus to EGF-R (425-s11) or to epithelial cell adhesion molecule (C28-s11) antigens. Moreover, a fiber modified adenovirus targeting alpha(v)-integrins was studied. Replication competent serotype-5 adenoviruses attenuated to replicate specifically in retinoblastoma pRb (Ad5-d24) or p53 deficient (Ad5-d55K) cells were tested in vitro for oncolytic properties. RESULTS: Low to absent Coxsackievirus and adenovirus receptor expression was found in 5 of the 7 tumor lines (SW800, J82, T24, 5637 and Scaber). EGF-R expression was found in all cell lines, whereas elevated epithelial cell adhesion molecule expression was seen in 3 (5637, Scaber and TCCsup), alpha(v)beta3-integrin was found in 1 (Scaber) and alpha(v)beta5-integrin was found in 3 (TCCsup, 253J and T24). EGF-R targeting using 425-s11 improved transgene expression in all cell lines from 2.1 to 12.5 times over nontargeted viruses. Epithelial cell adhesion molecule and integrin targeting was inferior to EGF-R targeting with a maximal increase in transgene expression of 2 times for epithelial cell adhesion molecule in 5637cells and 1.6 times for integrin targeting in T24 cells. Comparison of the wild-type replication competent virus with conditionally replicating adenoviruses (Ad5-d55K and Ad5-d24) showed superior oncolytic activity for the latter 2 in all lines. Furthermore, improved cytotoxicity (29% to 33%) was obtained in 4 of the 7 lines after pre-incubation of Ad5-d24 with 425-s11. CONCLUSIONS: EGF-R directed bispecific single chain antibodies enhance adenovirus mediated transgene expression and oncolysis in bladder cancer lines.

Published
2002

39. Combined targeting of adenoviruses to integrins and epidermal growth factor receptors increases gene transfer into primary glioma cells and spheroids

Author

Grill, Jacques, Van Beusechem, V W, Van Der Valk, P, Dirven, C M, Leonhart, A, Pherai, D S, Haisma, H J, Pinedo, H M, Curiel, D T, Gerritsen, W R, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Medical oncology laboratory, CCA - Cancer biology and immunology, Pathology, Amsterdam Neuroscience - Neuroinfection & -inflammation, CCA - Imaging and biomarkers, AII - Infectious diseases, NCA - Neuroinflamation, Neurosurgery, and Medical oncology

Subjects
EXPRESSION, DELIVERY, BRAIN-TUMORS, NECK-CANCER, COXSACKIE, INFECTION, VECTORS, HETEROGENEITY, CANCER CELLS, THERAPY
Abstract

Adenoviral-mediated gene transfer is suboptimal in human glioma and limits in vivo gene therapy approaches. There is a need for targeted vectors able to enhance gene transfer into the tumor as well as to lower the viral load in the surrounding normal tissues. We evaluated primary human tumor samples by immunohistochemistry and fluorescence-activated cell sorter for expression of the Coxsackie-adenovirus receptor and other antigens with potential utility to redirect adenoviruses (Ads) to gliomas. In the majority of the samples, Coxsackie-adenovirus receptor expression was low. This correlated with inefficient gene transfer in vitro. Epidermal growth factor receptor (EGFR) and alpha(v)beta5 integrins were often highly, but heterogeneously, expressed. We hypothesized that these receptors, overexpressed in tumor but not in normal brain, could serve as independent binding sites for alternative pathways of infection with targeted Ads. We examined this, using Ads that expressed the luciferase reporter gene under the cytomegalovirus promoter. Targeting to the EGFR was performed with a single-chain bispecific antibody directed against the human EGFR and against the fiber knob of the Ad. Targeting to the alpha(v) integrins was performed by insertion of an integrin-binding sequence, RGD-4C, in the HI-loop of the Ad. Increased luciferase gene transfer in primary glioma cells was observed in 8 of 13 samples with EGFR-targeting (2-11 times enhancement; median, 6) and in all of the samples with RGD-targeting (2-42 times enhancement; median, 12). Combining the two targeting motifs further enhanced the gene transfer in primary glioma cells in an additive manner (3-56 times; median, 20). The double-targeted Ads also strongly augmented gene transfer into organotypic glioma spheroids. Conversely, gene transfer into normal brain explants was reduced dramatically using Ads targeted to the tumor. Our findings demonstrate the feasibility and benefit of binding multiple ligands to the adenoviral fiber knob. These vectors have a great potential for clinical use in the context of tumors that are usually heterogeneous for target antigen expression at the single-cell level.

Published
2001

40. Liposomal targeting of peptides and proteins

Author

Storm, G., 't Hart, B.A., de Vries, R.R.P., Vingerhoeds, M.H., Haisma, H., Heeremans, A., Kluft, C., and Crommelin, D.J.A.

Subjects
Agrotechnological Research Institute, Life Science, Instituut voor Agrotechnologisch Onderzoek
Published
1996

44. Human IgM monoclonal antibody 16.88: pharmacokinetics and distribution in mouse and man

Author

Haisma, H. J., Kessel, M. A., Silva, C., van Muijen, M., Roos, J. C., Bril, H., Martens, H. J., McCabe, R., and Boven, E.

Subjects
Mice, Immunoglobulin M, Colonic Neoplasms, Animals, Antibodies, Monoclonal, Humans, Mice, Nude, Research Article
Abstract

Human IgM monoclonal antibody (MAb) 16.88 recognizes an antigen strongly expressed by colon cancer tissue. We used 131I-labelled 16.88 for biodistribution and pharmacokinetic studies in nude mice bearing WiDr or NIH:OVCAR-3 xenografts. Serum half-life was 8 h. Maximum tumour uptake was between 1 and 8 h after administration and amounted to, respectively, 3% and 1% of the injected dose g-1 for WiDr and NIH:OVCAR-3 tumours. Half-lives in these tumours were approximately 24 h. Tumour to normal colon uptake ratios increased from 2.3 at 24 h to 17 at 5 days after injection. Simultaneously, pharmacokinetic studies were performed in patients with advanced colon cancer reactive with 16.88. They were injected with 5 mCi 131I-16.88 by intravenous infusion over 2 h. Serum half-life was 20 h with greater than 90% of the 131I bound to 16.88. Within 40 h 50% of the injected dose was excreted as free 131I in the urine. In one patient an accelerated clearance was found, possibly caused by pre-existing antibodies reacting with 16.88. None of the patients showed an immune response against 16.88 antibody. Immunoscintigraphy showed positive tumour localization in the majority of the patients, best visualized at later days. We conclude that 16.88 has tumour localization properties while its human origin accounts for the lack of immunogenicity.

Published
1990

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