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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">ssmu</journal-id><journal-title-group><journal-title xml:lang="ru">Бюллетень сибирской медицины</journal-title><trans-title-group xml:lang="en"><trans-title>Bulletin of Siberian Medicine</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">1682-0363</issn><issn pub-type="epub">1819-3684</issn><publisher><publisher-name>Siberian State Medical University, the Ministry of Healthcare of the Russian Federation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.20538/1682-0363-2018-3-188-196</article-id><article-id custom-type="elpub" pub-id-type="custom">ssmu-1298</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОБЗОРЫ И ЛЕКЦИИ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>REVIEW AND LECTURES</subject></subj-group></article-categories><title-group><article-title>Двухмерные и трехмерные модели культур клеток опухолей in vitro:  преимущества и недостатки</article-title><trans-title-group xml:lang="en"><trans-title>Two-dimensional and three-dimensional cell culture models in vitro:  pros and cons</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Галимова</surname><given-names>Э. С.</given-names></name><name name-style="western" xml:lang="en"><surname>Galimova</surname><given-names>E. S.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Галимова Эльвира Сафуановна - кандидат биологических наук, старший научный сотрудник, отдел биохимических исследований, Центр доклинических и трансляционных исследований, Институт ýкспериментальной медицины.</p><p>197341, Санкт-Петербург, ул. Аккуратова, 2</p></bio><bio xml:lang="en"><p>Galimova Elvira S. -  PhD, Senior Researcher.</p><p>2, Accuratov Str., Saint Petersburg, 197341</p></bio><email xlink:type="simple">elya-4@yandex.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Галагудза</surname><given-names>М. М.</given-names></name><name name-style="western" xml:lang="en"><surname>Galagudza</surname><given-names>M. М.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Галагудза Михаил Михайлович - докторр медицинских наук, член-корр. РАН, директор Института ýкспериментальной медицины.</p><p>197341, Санкт-Петербург, ул. Аккуратова, 2</p></bio><bio xml:lang="en"><p>Galagudza  Michael M. - DM., Professor, Head of Institute of Experimental Medicine.</p><p>2, Accuratov Str., Saint Petersburg, 197341</p></bio><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>Национальный медицинский исследовательский центр (НМИЦ) им. В.А. Алмазова</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Almazov National Medical Research Center</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2018</year></pub-date><pub-date pub-type="epub"><day>29</day><month>09</month><year>2018</year></pub-date><volume>17</volume><issue>3</issue><fpage>188</fpage><lpage>196</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Галимова Э.С., Галагудза М.М., 2018</copyright-statement><copyright-year>2018</copyright-year><copyright-holder xml:lang="ru">Галимова Э.С., Галагудза М.М.</copyright-holder><copyright-holder xml:lang="en">Galimova E.S., Galagudza M.М.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://bulletin.ssmu.ru/jour/article/view/1298">https://bulletin.ssmu.ru/jour/article/view/1298</self-uri><abstract><p>Синтез и внедрение новых химических соединений, обладающих потенциальной противоопухолевой активностью, требуют надежных предиктивных доклинических моделей для скрининга эффективности in vitro. Такие модели включают культуры клеток опухолей человека – двухмерные системы культур клеток 2D (two-dimensional cell culture systems) и трехмерные системы культур клеток 3D (three-dimensional cell culture systems). В этом обзоре обсуждаются особенности молекулярного фенотипа клеток, культивируемых в 2Dand 3D-системах, и их применение в исследованиях эффективности противоопухолевых препаратов с упором на ключевые примеры из научной литературы. В обзоре также проанализированы преимущества, недостатки и перспективы применения описываемых моделей культур опухолевых клеток.</p></abstract><trans-abstract xml:lang="en"><p>Discovery and development of new chemical compounds with putative anti-cancer properties requires reliable predictive preclinical models for in vitro screening of efficacy. Such models mainly include cultures of human cancer cells: two-dimensional (2D) and three-dimensional (3D) cell culture systems. In this review, we discuss the molecular aspects of cells cultured in 2D and 3D, and their relevance to cancer study, focusing on key examples from the recent literature. Advantages, disadvantages and perspectives of described models are also analyzed.</p></trans-abstract><kwd-group xml:lang="ru"><kwd>рак</kwd><kwd>доклиническая модель</kwd><kwd>2Dи 3D-модели культур клеток</kwd><kwd>культура клеток</kwd><kwd>скрининг эффективности препаратов in vitro</kwd></kwd-group><kwd-group xml:lang="en"><kwd>cancer</kwd><kwd>preclinical model</kwd><kwd>2D and 3D cell culture</kwd><kwd>screening of drug efficacy in vitro</kwd></kwd-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Kola I., Landis J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Dis. 2004; 3 (8): 711–715. DOI: 10.1038/nrd1470.</mixed-citation><mixed-citation xml:lang="en">Kola I., Landis J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Dis. 2004; 3 (8): 711–715. DOI: 10.1038/nrd1470.</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Amelian A., Wasilewska K., Megias D., Winnicka K. Application of standard cell cultures and 3D in vitro tissue models as an effective tool in drug design and development. Pharmacological Reports. 2017; 69 (5): 861–870. DOI: 10.1016/j.pharep.2017.03.014.</mixed-citation><mixed-citation xml:lang="en">Amelian A., Wasilewska K., Megias D., Winnicka K.  Application of standard cell cultures and 3D in vitro tissue models as an effective tool in drug design and development. Pharmacological Reports. 2017; 69 (5): 861–870. DOI: 10.1016/j.pharep.2017.03.014.</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Santo V.E., Rebelo S.P., Estrada M.F., Alves P.M., Boghaert E., &amp; Brito C. Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read – outs. Biotechnology journal. 2017; 12 (1). DOI: 10.1002/biot.201600505.</mixed-citation><mixed-citation xml:lang="en">Santo V.E., Rebelo S.P., Estrada M.F., Alves P.M., Boghaert E., &amp; Brito C. Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read – outs. Biotechnology journal. 2017; 12 (1).  DOI: 10.1002/ biot.201600505.</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Fong E.L., Harrington D.A., Farach-Carson M.C., Yu.H. Heralding a new paradigm in 3D tumor modeling. Biomaterials. 2016; 108: 197–213. DOI: 10.1016/j.biomaterials.2016.08.052.</mixed-citation><mixed-citation xml:lang="en">Fong E.L., Harrington D.A., Farach-Carson M.C., Yu.H. Heralding a new paradigm in 3D tumor modeling. Biomaterials. 2016; 108: 197–213.  DOI: 10.1016/j.biomaterials.2016.08.052.</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Duval K., Grover H., Han L.H., Mou Y., Pegoraro A.F., Fredberg J., Chen Z. Modeling Physiological Events in 2D vs. 3D Cell Culture. Physiology. 2017; 32 (4): 266–277. DOI: 10.1152/physiol.00036.2016.</mixed-citation><mixed-citation xml:lang="en">Duval K., Grover H., Han  L.H., Mou Y., Pegoraro A.F., Fredberg J., Chen Z. Modeling Physiological Events in 2D vs. 3D Cell Culture. Physiology. 2017; 32 (4): 266–277.  DOI: 10.1152/physiol.00036.2016.</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Lovitt C.J., Shelper T.B., Avery V.M. Advanced cell culture techniques for cancer drug discovery. Biology. 2014; 3 (2): 345–367. DOI: 10.3390/biology3020345.</mixed-citation><mixed-citation xml:lang="en">Lovitt C.J., Shelper T.B., Avery V.M. Advanced cell culture techniques for cancer drug discovery. Biology. 2014; 3 (2): 345–367.  DOI: 10.3390/biology3020345.</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Edmondson R., Broglie J.J., Adcock A.F., Yang L. Threedimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay and drug development technologies. 2014; 12 (4): 207–218. DOI: 10.1089/adt.2014.573.</mixed-citation><mixed-citation xml:lang="en">Edmondson R., Broglie J.J., Adcock A.F., Yang L. Threedimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay and drug development technologies. 2014; 12 (4): 207–218. DOI: 10.1089/adt.2014.573.</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Tibbitt M.W., Anseth K.S. Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnology and bioengineering. 2009; 103 (4): 655–663. DOI: 10.1002/bit.22361.</mixed-citation><mixed-citation xml:lang="en">Tibbitt M.W., Anseth  K.S. Hydrogels as extracellular matrix mimics for 3D cell culture.  Biotechnology and bioengineering. 2009; 103 (4): 655–663. DOI: 10.1002/bit.22361.</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Bi Y.A., Kazolias D., Duignan D.B. Use of cryopreserved human hepatocytes in sandwich culture to measure hepatobiliary transport. Drug Metab. Dispos. 2006; 34: 1658–1665. DOI: 10.1124/dmd.105.009118.</mixed-citation><mixed-citation xml:lang="en">Bi Y.A., Kazolias D., Duignan D.B. Use of cryopreserved human hepatocytes in sandwich culture to measure hepatobiliary transport. Drug Metab. Dispos. 2006; 34: 1658–1665.  DOI: 10.1124/dmd.105.009118.</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Dunn J.C.Y., Tompkins R.G., Yarmush M.L. Hepatocytes in collagen sandwich: evidence for transcriptional and translational regulation. J. Cell Biol. 1992; 116 (4): 1043–1053. DOI: 10.1083/jcb.116.4.1043.</mixed-citation><mixed-citation xml:lang="en">Dunn J.C.Y., Tompkins R.G., Yarmush M.L. Hepatocytes in collagen sandwich: evidence for transcriptional and translational regulation. J. Cell Biol. 1992; 116 (4): 1043–1053. DOI: 10.1083/jcb.116.4.1043.</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Ezzell R.M., Toner M., Hendricks K., Dunn J.C., Tompkins R.G., Yarmush M.L.. Effect of collagen gel configuration on the cytoskeleton in cultured rat hepatocytes. Exp. Cell Res. 1993; 208: 442–452. DOI: 10.1006/excr.1993.1266.</mixed-citation><mixed-citation xml:lang="en">Ezzell R.M., Toner M., Hendricks K., Dunn J.C., Tompkins R.G., Yarmush M.L.. Effect of collagen gel configuration on the cytoskeleton in cultured rat hepatocytes. Exp. Cell Res. 1993; 208: 442–452.  DOI: 10.1006/excr.1993.1266.</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Jones H.M., Barton H.A., Lai Y., Bi Y.A., Kimoto E., Kempshall S., Tate S.C., El-Kattan A., Houston J.B., Galetin A., Fenner K.S.. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug Metab. Dispos. 2012; 40 (5): 1007–1017. DOI: 10.1124/dmd.111.042994.</mixed-citation><mixed-citation xml:lang="en">Jones H.M., Barton H.A., Lai Y., Bi Y.A., Kimoto E., Kempshall S., Tate S.C., El-Kattan A., Houston J.B., Galetin A., Fenner K.S.. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug Metab. Dispos. 2012; 40 (5): 1007–1017.  DOI: 10.1124/dmd.111.042994.</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">LeCluyse E.L., Audus K.L., Hochman J.H. Formation of extensive canalicular networks by rat hepatocytes cultured in collagen-sandwich configuration. Am. J. Physiol. 1994; 266: C1764–C1774.</mixed-citation><mixed-citation xml:lang="en">LeCluyse E.L., Audus K.L., Hochman J.H. Formation of extensive canalicular networks by rat hepatocytes cultured in collagen-sandwich configuration. Am. J. Physiol. 1994; 266: C1764–C1774.</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Price K.J., Tsykin A., Giles K.M., Sladic R.T., Epis M.R., Ganss R., Goodall G.L., Leedman P.J. Matrigel basement membrane matrix influences expression of microRNAs in cancer cell lines. Biochem. Biophys. Res. Commun. 2012; 427 (2): 343–348. DOI: 10.1016/j.bbrc.2012.09.059.</mixed-citation><mixed-citation xml:lang="en">Price K.J., Tsykin A., Giles K.M., Sladic R.T., Epis M.R., Ganss R., Goodall G.L., Leedman P.J. Matrigel basement membrane matrix influences expression of microRNAs in cancer cell lines. Biochem. Biophys. Res. Commun.  2012; 427 (2): 343–348. DOI: 10.1016/j.bbrc.2012.09.059.</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Loessner D., Stok K.S., Lutolf M.P., Hutmacher D.W., Clements J.A., Rizzi S.C. Bioengineered 3D platform to explore cell–ECM interactions and drug resistance of epithelial ovarian cancer cells. Biomaterials. 2010; 31 (32): 8494– 8506. DOI: 10.1016/j.biomaterials.2010.07.064.</mixed-citation><mixed-citation xml:lang="en">Loessner D., Stok K.S., Lutolf M.P., Hutmacher D.W., Clements J.A., Rizzi S.C. Bioengineered 3D platform to explore cell–ECM interactions and drug resistance of epithelial ovarian cancer cells. Biomaterials. 2010; 31 (32): 8494– 8506.  DOI: 10.1016/j.biomaterials.2010.07.064.</mixed-citation></citation-alternatives></ref><ref id="cit16"><label>16</label><citation-alternatives><mixed-citation xml:lang="ru">Luca A.C., Mersch S., Deenen R., Schmidt S., Messner I., Schafer K.L., Baldus S.E., Huckenbeck W., Piekorz R.P., Wolfram T., Knoefel W.T., Krieg A., Stoecklein N.H. Impact of the 3D microenvironment on phenotype, gene expression, and EGFR inhibition of colorectal cancer cell lines. PLoS One. 2013; 8 (3): e59689. DOI: 10.1371/journal.pone.0059689</mixed-citation><mixed-citation xml:lang="en">Luca A.C., Mersch S., Deenen R., Schmidt S., Messner I., Schafer K.L., Baldus S.E., Huckenbeck W., Piekorz R.P., Wolfram T., Knoefel W.T., Krieg A.,  Stoecklein N.H. Impact of the 3D microenvironment on phenotype, gene expression, and EGFR inhibition of colorectal cancer cell lines. PLoS One. 2013; 8 (3): e59689.  DOI: 10.1371/journal.pone.0059689</mixed-citation></citation-alternatives></ref><ref id="cit17"><label>17</label><citation-alternatives><mixed-citation xml:lang="ru">Shield K., Ackland M.L., Ahmed N., Rice G.E. Multicellular spheroids in ovarian cancer metastases: biology and pathology. Gynecol. Oncol. 2009; 113 (1): 143–148. DOI: 10.1016/j.ygyno.2008.11.032.</mixed-citation><mixed-citation xml:lang="en">Shield K., Ackland M.L., Ahmed N., Rice G.E. Multicellular spheroids in ovarian cancer metastases: biology and pathology. Gynecol. Oncol. 2009; 113 (1): 143–148. DOI: 10.1016/j.ygyno.2008.11.032.</mixed-citation></citation-alternatives></ref><ref id="cit18"><label>18</label><citation-alternatives><mixed-citation xml:lang="ru">Zietarska M., Maugard C.M., Filali-Mouhim A., AlamFahmy M., Tonin P.N., Provencher D.M., Mes-Masson A.M. Molecular description of a 3D in vitro model for the study of epithelial ovarian cancer (EOC). Mol. Carcinog. 2007; 46 (10): 872–885. DOI: 10.1002/mc.20315.</mixed-citation><mixed-citation xml:lang="en">Zietarska M., Maugard C.M., Filali-Mouhim A., AlamFahmy M., Tonin P.N., Provencher D.M., Mes-Masson A.M. Molecular description of a 3D in vitro model for the study of epithelial ovarian cancer (EOC). Mol. Carcinog. 2007; 46 (10): 872–885. DOI: 10.1002/mc.20315.</mixed-citation></citation-alternatives></ref><ref id="cit19"><label>19</label><citation-alternatives><mixed-citation xml:lang="ru">Lee J., Cuddihy M.J., Kotov N.A. Three-dimensional cell culture matrices: state of the art. Tissue Eng. Part B Rev. 2008; 14 (1): 61–86. DOI: 10.1089/teb.2007.0150.</mixed-citation><mixed-citation xml:lang="en">Lee J., Cuddihy M.J., Kotov N.A. Three-dimensional cell culture matrices: state of the art. Tissue Eng. Part B Rev. 2008; 14 (1): 61–86. DOI: 10.1089/teb.2007.0150.</mixed-citation></citation-alternatives></ref><ref id="cit20"><label>20</label><citation-alternatives><mixed-citation xml:lang="ru">Karlsson H., Fryknäs M., Larsson R., Nygren P. Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system. Exper. Cell Res. 2012; 318 (13): 1577–1585. DOI: 10.1016/j.yexcr.2012.03.026.</mixed-citation><mixed-citation xml:lang="en">Karlsson H., Fryknäs M., Larsson R., Nygren P. Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system. Exper. Cell Res. 2012; 318 (13): 1577–1585. DOI: 10.1016/j.yexcr.2012.03.026.</mixed-citation></citation-alternatives></ref><ref id="cit21"><label>21</label><citation-alternatives><mixed-citation xml:lang="ru">Elliott N.T., Yuan F. A review of three-dimensional in vitro tissue models for drug discovery and transport studies. J. Pharm. Sci. 2010; 100 (1): 59–74. DOI: 10.1002/jps.22257.</mixed-citation><mixed-citation xml:lang="en">Elliott N.T., Yuan F. A review of three-dimensional in vitro tissue models for drug discovery and transport studies. J. Pharm. Sci. 2010; 100 (1): 59–74.  DOI: 10.1002/jps.22257.</mixed-citation></citation-alternatives></ref><ref id="cit22"><label>22</label><citation-alternatives><mixed-citation xml:lang="ru">Walker D.M., Boey G., McDonald L.A. The pathology of oral cancer. Pathology. 2003; 35 (5): 376–383.</mixed-citation><mixed-citation xml:lang="en">Walker D.M., Boey G., McDonald L.A. The pathology of oral cancer. Pathology. 2003; 35 (5): 376–383.</mixed-citation></citation-alternatives></ref><ref id="cit23"><label>23</label><citation-alternatives><mixed-citation xml:lang="ru">Trédan O., Galmarini C.M., Patel K., Tannock I.F. Drug resistance and the solid tumor microenvironment. J. Nat. Cancer Inst. 2007; 99 (19): 1441–1454. DOI: 10.1093/jnci/djm135.</mixed-citation><mixed-citation xml:lang="en">Trédan O., Galmarini C.M., Patel K., Tannock I.F. Drug resistance and the solid tumor microenvironment. J. Nat. Cancer Inst. 2007; 99 (19): 1441–1454.  DOI: 10.1093/jnci/djm135.</mixed-citation></citation-alternatives></ref><ref id="cit24"><label>24</label><citation-alternatives><mixed-citation xml:lang="ru">Sodek K.L., Ringuette M.J., Brown T.J. Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype. Int. J. Cancer. 2009; 124 (9): 2060–2070. DOI: 10.1002/ijc.24188.</mixed-citation><mixed-citation xml:lang="en">Sodek K.L., Ringuette M.J., Brown T.J. Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype. Int. J. Cancer. 2009; 124 (9): 2060–2070. DOI: 10.1002/ijc.24188.</mixed-citation></citation-alternatives></ref><ref id="cit25"><label>25</label><citation-alternatives><mixed-citation xml:lang="ru">Yip D., Cho C.H. A multicellular 3D heterospheroid model of liver tumor and stromal cells in collagen gel for anti-cancer drug testing. Biochem. Biophys. Res. Commun. 2013; 433 (3): 327–332. DOI: 10.1016/j.bbrc.2013.03.008.</mixed-citation><mixed-citation xml:lang="en">Yip D., Cho C.H. A multicellular 3D heterospheroid model of liver tumor and stromal cells in collagen gel for anti-cancer drug testing. Biochem. Biophys. Res. Commun. 2013; 433 (3): 327–332. DOI: 10.1016/j.bbrc.2013.03.008.</mixed-citation></citation-alternatives></ref><ref id="cit26"><label>26</label><citation-alternatives><mixed-citation xml:lang="ru">Gurski L., Petrelli N., Jia X., Farach-Carson M. 3D matrices for anti-cancer drug testing and development. Oncol. Issues. 2010; 25 (1): 20–25.</mixed-citation><mixed-citation xml:lang="en">Gurski L., Petrelli N., Jia X., Farach-Carson M. 3D matrices for anti-cancer drug testing and development. Oncol. Issues. 2010; 25 (1): 20–25.</mixed-citation></citation-alternatives></ref><ref id="cit27"><label>27</label><citation-alternatives><mixed-citation xml:lang="ru">Wen Z., Liao Q., Hu Y., You L., Zhou L., Zhao Y. A spheroid-based 3-D culture model for pancreatic cancer drug testing, using the acid phosphatase assay. Braz. J. Med. Biol. Res. 2013; 46 (7): 634–642. DOI: 10.1590/1414-431X20132647.</mixed-citation><mixed-citation xml:lang="en">Wen Z., Liao Q., Hu Y., You L., Zhou L., Zhao Y. A spheroid-based 3-D culture model for pancreatic cancer drug testing, using the acid phosphatase assay. Braz. J. Med. Biol. Res. 2013; 46 (7): 634–642. DOI: 10.1590/1414-431X20132647.</mixed-citation></citation-alternatives></ref><ref id="cit28"><label>28</label><citation-alternatives><mixed-citation xml:lang="ru">Tung Y.C., Hsiao A.Y., Allen S.G., Torisawa Y., Ho M., Takayama S. High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst. 2011; 136 (3): 473–478. DOI: 10.1039/c0an00609b.</mixed-citation><mixed-citation xml:lang="en">Tung Y.C., Hsiao A.Y., Allen S.G., Torisawa Y., Ho M., Takayama S. High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst. 2011; 136 (3): 473–478. DOI: 10.1039/c0an00609b.</mixed-citation></citation-alternatives></ref><ref id="cit29"><label>29</label><citation-alternatives><mixed-citation xml:lang="ru">Chitcholtan K., Sykes P., Evans J. The resistance of intracellular mediators to doxorubicin and cisplatin aredistinct in 3D and 2D endometrial cancer. J. Transl. Med. 2012; 10: 1–16. DOI: 10.1186/1479-5876-10-38.</mixed-citation><mixed-citation xml:lang="en">Chitcholtan K., Sykes P., Evans J. The resistance of intracellular mediators to doxorubicin and cisplatin aredistinct in 3D and 2D endometrial cancer. J. Transl. Med. 2012; 10: 1–16. DOI:  10.1186/1479-5876-10-38.</mixed-citation></citation-alternatives></ref><ref id="cit30"><label>30</label><citation-alternatives><mixed-citation xml:lang="ru">Swietach P., Hulikova A., Patiar S., Vaughan-Jones R.D., Harris A.L. Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS One. 2012; 7: e35949.</mixed-citation><mixed-citation xml:lang="en">Swietach P., Hulikova A., Patiar S., Vaughan-Jones R.D., Harris A.L. Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS One. 2012; 7: e35949.</mixed-citation></citation-alternatives></ref><ref id="cit31"><label>31</label><citation-alternatives><mixed-citation xml:lang="ru">Nam J.M., Onodera Y., Bissell M.J., Park C.C. Breast cancer cells in three-dimensional culture display an enhanced radioresponse after coordinate targeting of integrin α5β1 and fibronectin. Cancer Res. 2010; 70 (13): 5238–5248. DOI: 10.1158/0008-5472.CAN-09-2319.</mixed-citation><mixed-citation xml:lang="en">Nam J.M., Onodera Y., Bissell M.J., Park C.C. Breast cancer cells in three-dimensional culture display an enhanced radioresponse after coordinate targeting of integrin α5β1 and fibronectin. Cancer Res. 2010; 70 (13): 5238–5248. DOI: 10.1158/0008-5472.CAN-09-2319.</mixed-citation></citation-alternatives></ref><ref id="cit32"><label>32</label><citation-alternatives><mixed-citation xml:lang="ru">Michaylira C.Z., Wong G.S., Miller C.G., Gutierrez C.M., Nakagawa H., Hammond R., Klein-Szanto A.J., Lee J.S., Kim S.B., Herlyn M., Diehl J.A., Gimotty P, Rustgi A.K. Periostin, a cell adhesion molecule, facilitates invasion in the tumor microenvironment and annotates a novel tumor-invasive signature in esophageal cancer. Cancer Res. 2010; 70 (13): 5281–5292. DOI: 10.1158/0008-5472.CAN-10-0704.</mixed-citation><mixed-citation xml:lang="en">Michaylira C.Z., Wong G.S., Miller C.G., Gutierrez C.M., Nakagawa H., Hammond R., Klein-Szanto A.J., Lee J.S., Kim S.B., Herlyn M., Diehl J.A., Gimotty P, Rustgi A.K. Periostin, a cell adhesion molecule, facilitates invasion in the tumor microenvironment and annotates a novel tumor-invasive signature in esophageal cancer. Cancer Res. 2010; 70 (13): 5281–5292. DOI: 10.1158/0008-5472.CAN-10-0704.</mixed-citation></citation-alternatives></ref><ref id="cit33"><label>33</label><citation-alternatives><mixed-citation xml:lang="ru">Kondo J., Endo H., Okuyama H., Ishikawac O., Iishid H., Tsujiib M., Ohuec M., Inoue M. Retaining cell–cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer. Proc. Natl. Acad. Sci. USA. 2011; 108 (15): 6235–6240. DOI: 10.1073/pnas.1015938108/.</mixed-citation><mixed-citation xml:lang="en">Kondo J., Endo H., Okuyama H., Ishikawac O., Iishid H., Tsujiib M., Ohuec M., Inoue M. Retaining cell–cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer. Proc. Natl. Acad. Sci. USA. 2011; 108 (15): 6235–6240. DOI:  10.1073/pnas.1015938108/.</mixed-citation></citation-alternatives></ref><ref id="cit34"><label>34</label><citation-alternatives><mixed-citation xml:lang="ru">Praveen K., Streiner N., Vo M., Anderes K., Yokota K., Ikeya T. Evaluation of Cell-able spheroid culture system for culturing patient derived primary tumor cells. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. Cancer Res. 2012; 72 (8 Suppl): 5270 [Abstract].</mixed-citation><mixed-citation xml:lang="en">Praveen K., Streiner N., Vo M., Anderes K., Yokota K., Ikeya T. Evaluation of Cell-able spheroid culture system for culturing patient derived primary tumor cells. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. Cancer Res. 2012; 72 (8 Suppl): 5270 [Abstract].</mixed-citation></citation-alternatives></ref><ref id="cit35"><label>35</label><citation-alternatives><mixed-citation xml:lang="ru">Fiebig H: Oncotest. www.oncotest.com/id-3d-assays.html (last accessed on April 11, 2014).</mixed-citation><mixed-citation xml:lang="en">Fiebig H: Oncotest. www.oncotest.com/id-3d-assays.html (last accessed on April 11, 2014).</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
