Abstract
The development of therapeutics to treat cancer is conceptually more difficult than for nonlife-threatening diseases for several reasons, including its complex pathophysiological nature, the molecular individuality of each tumor, and the robustness and predictability of preclinical models toward determining efficacy and safety. A major limitation to development of a “blockbuster” therapeutic strategy is the infinite combination of cellular and molecular perturbations and associated heterogeneity of causative genetic factors driving disease progression. Although challenging, the diversity of drug targets, coupled with the lethality of the disease, has encouraged studies of a vast array of approaches and opportunities for disease treatment over the years.
Similar content being viewed by others
References and Further Reading
Assessment of Cellular Toxicity: MTT Assay
Cavanaugh PF Jr, Moskwa PS, Donish WH, Pera PJ, Richardson D, Andrese AP (1990) A semi-automated neutral red based chemosensitivity assay for drug screening. Invest New Drugs 8:347–354
Cho MH, Niles A, Huang R, Inglese J, Austin CP, Riss T et al (2008) A bioluminescent cytotoxicity assay for assessment of membrane integrity using a proteolytic biomarker. Toxicol In Vitro 22:1099–1106
Crouch SP, Kozlowski R, Slater KJ, Fletcher J (1993) The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity. J Immunol Methods 160:81–88
Hamid R, Rotshteyn Y, Rabadi L, Parikh R, Bullock P (2004) Comparison of alamar blue and MTT assays for high through-put screening. Toxicol In Vitro 18:703–710
Holbeck SL, Collins JM, Doroshow JH (2010) Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines. Mol Cancer Ther 9:1451–1460
Khoshmanesh K, Akagi J, Nahavandi S, Skommer J, Baratchi S, Cooper JM et al (2011) Dynamic analysis of drug-induced cytotoxicity using chip-based dielectrophoretic cell immobilization technology. Anal Chem 83:2133–2144
Limame R, Wouters A, Pauwels B, Fransen E, Peeters M, Lardon F et al (2012) Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays. PloS One 7:e46536
McKim JM Jr (2010) Building a tiered approach to in vitro predictive toxicity screening: a focus on assays with in vivo relevance. Comb Chem High Throughput Screen 13:188–206
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Park G, Choi CK, English AE, Sparer TE (2009) Electrical impedance measurements predict cellular transformation. Cell Biol Int 33:429–433
Roshan Moniri M, Young A, Reinheimer K, Rayat J, Dai LJ, Warnock GL (2015) Dynamic assessment of cell viability, proliferation and migration using real time cell analyzer system (RTCA). Cytotechnology 67:379–386
Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH et al (1988) Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 48:4827–4833
Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–823
Shukla SJ, Huang R, Austin CP, Xia M (2010) The future of toxicity testing: a focus on in vitro methods using a quantitative high-throughput screening platform. Drug Discov Today 15:997–1007
Cell Scratch “Wound-Healing” Assay
Al-Saraireh YM, Sutherland M, Springett BR, Freiberger F, Ribeiro Morais G, Loadman PM et al (2013) Pharmacological inhibition of polysialyltransferase ST8SiaII modulates tumour cell migration. PLoS One 8:e73366
Elbjeirami WM, West JL (2006) Angiogenesis-like activity of endothelial cells co-cultured with VEGF-producing smooth muscle cells. Tissue Eng 12:381–390
Fougerat A, Smirnova NF, Gayral S, Malet N, Hirsch E, Wymann MP et al (2012) Key role of PI3Kgamma in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration. Br J Pharmacol 166:1643–1653
George M, Vaughan JH (1962) In vitro cell migration as a model for delayed hypersensitivity. Proc Soc Exp Biol Med 111:514–521
Gorshkova I, He D, Berdyshev E, Usatuyk P, Burns M, Kalari S et al (2008) Protein kinase C-epsilon regulates sphingosine 1-phosphate-mediated migration of human lung endothelial cells through activation of phospholipase D2, protein kinase C-zeta, and Rac1. J Biol Chem 283:11794–11806
Kramer N, Walzl A, Unger C, Rosner M, Krupitza G, Hengstschlager M et al (2013) In vitro cell migration and invasion assays. Mutat Res 752:10–24
Liang CC, Park AY, Guan JL (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2:329–333
Lingen MW (2003) Endothelial cell migration assay. A quantitative assay for prediction of in vivo biology. Methods Mol Med 78:337–347
Lo CM, Keese CR, Giaever I (1993) Monitoring motion of confluent cells in tissue culture. Exp Cell Res 204:102–109
Menon MB, Ronkina N, Schwermann J, Kotlyarov A, Gaestel M (2009) Fluorescence-based quantitative scratch wound healing assay demonstrating the role of MAPKAPK-2/3 in fibroblast migration. Cell Motil Cytoskeleton 66:1041–1047
Poujade M, Grasland-Mongrain E, Hertzog A, Jouanneau J, Chavrier P, Ladoux B et al (2007) Collective migration of an epithelial monolayer in response to a model wound. Proc Natl Acad Sci U S A 104:15988–15993
Roshan Moniri M, Young A, Reinheimer K, Rayat J, Dai LJ, Warnock GL (2015) Dynamic assessment of cell viability, proliferation and migration using real time cell analyzer system (RTCA). Cytotechnology 67:379–386
Takaishi K, Sasaki T, Takai Y (1995) Cell motility assay and inhibition by Rho-GDP dissociation inhibitor. Methods Enzymol 256:336–347
Zicha D, Dunn GA, Brown AF (1991) A new direct-viewing chemotaxis chamber. J Cell Sci 99(Pt 4):769–775
Microwell Boyden Chamber for Cancer Cell Invasion
Albini A, Noonan DM (2010) The ‘chemoinvasion’ assay, 25 years and still going strong: the use of reconstituted basement membranes to study cell invasion and angiogenesis. Curr Opin Cell Biol 22:677–689
Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlowski JM et al (1987) A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res 47:3239–3245
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L et al (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16:183–194
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Hart IR, Fidler IF (1978) An in vitro quantitative assay for tumor cell invasion. Cancer Res 38:3218–3224
Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252
Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401
Kleinman HK, McGarvey ML, Hassell JR, Star VL, Cannon FB, Laurie GW et al (1986) Basement membrane complexes with biological activity. Biochemistry 25:312–318
Limame R, Wouters A, Pauwels B, Fransen E, Peeters M, Lardon F et al (2012) Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays. PloS one 7:e46536
Marsh D, Dickinson S, Neill GW, Marshall JF, Hart IR, Thomas GJ (2008) alpha vbeta 6 Integrin promotes the invasion of morphoeic basal cell carcinoma through stromal modulation. Cancer Res 68:3295–3303
Mignatti P, Robbins E, Rifkin DB (1986) Tumor invasion through the human amniotic membrane: requirement for a proteinase cascade. Cell 47:487–498
Roshan Moniri M, Young A, Reinheimer K, Rayat J, Dai LJ, Warnock GL (2015) Dynamic assessment of cell viability, proliferation and migration using real time cell analyzer system (RTCA). Cytotechnology 67:379–386
Sasaki CY, Passaniti A (1998) Identification of anti-invasive but noncytotoxic chemotherapeutic agents using the tetrazolium dye MTT to quantitate viable cells in Matrigel. Biotechniques 24:1038–1043
Scrace S, O’Neill E, Hammond EM, Pires IM (2013) Use of the xCELLigence system for real-time analysis of changes in cellular motility and adhesion in physiological conditions. Methods Mol Biol 1046:295–306
Shaw LM (2005) Tumor cell invasion assays. Methods Mol Biol 294:97–105
Real-Time In Vitro Analysis of Cell Survival and Behaviour: Label-Free Technologies
Abassi YA, Xi B, Zhang W, Ye P, Kirstein SL, Gaylord MR et al (2009) Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects. Chem Biol 16:712–723
Adlam DJ, Dabbous MK, Woolley DE (2008) Electrochemical monitoring of rat mammary adenocarcinoma cells: an in vitro assay for anticancer drug selection. Assay Drug Dev Technol 6:795–802
Andreescu S, Sadik OA, McGee DW, Suye S (2004) Autonomous multielectrode system for monitoring the interactions of isoflavonoids with lung cancer cells. Anal Chem 76:2321–2330
Arias LR, Perry CA, Yang L (2010) Real-time electrical impedance detection of cellular activities of oral cancer cells. Biosens Bioelectron 25:2225–2231
Atienza JM, Yu N, Kirstein SL, Xi B, Wang X, Xu X et al (2006) Dynamic and label-free cell-based assays using the real-time cell electronic sensing system. Assay Drug Dev Technol 4:597–607
Bobacka J, Ivaska A, Lewenstam A (2008) Potentiometric ion sensors. Chem Rev 108:329–351
Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51
Boyden S (1962) The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J Exp Med 115:453–466
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S et al (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104:19345–19350
Dunne PD, McArt DG, Blayney JK, Kalimutho M, Greer S, Wang T et al (2014) AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer. Clin Cancer Res Off J Am Assoc Cancer Res 20:164–175
Ekelund S, Liminga G, Bjorkling F, Ottosen E, Schou C, Binderup L et al (2000) Early stimulation of acidification rate by novel cytotoxic pyridyl cyanoguanidines in human tumor cells: comparison with m-iodobenzylguanidine. Biochem Pharmacol 60:839–849
Franks W, Schenker I, Schmutz P, Hierlemann A (2005) Impedance characterization and modeling of electrodes for biomedical applications. IEEE Trans Bio-Med Eng 52:1295–1302
Gohil VM, Sheth SA, Nilsson R, Wojtovich AP, Lee JH, Perocchi F et al (2010) Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol 28:249–255
Hulkower KI, Herber RL (2011) Cell migration and invasion assays as tools for drug discovery. Pharmaceutics 3:107–124
Ke N, Xi B, Ye P, Xu W, Zheng M, Mao L et al (2010) Screening and identification of small molecule compounds perturbing mitosis using time-dependent cellular response profiles. Anal Chem 82:6495–6503
Ke N, Wang X, Xu X, Abassi YA (2011) The xCELLigence system for real-time and label-free monitoring of cell viability. Methods Mol Biol 740:33–43
Ke N, Nguyen K, Irelan J, Abassi YA (2015) Multidimensional GPCR profiling and screening using impedance-based label-free and real-time assay. Methods Mol Biol 1272:215–226
Kho D, MacDonald C, Johnson R, Unsworth CP, O’Carroll SJ, Mez E et al (2015) Application of xCELLigence RTCA biosensor technology for revealing the profile and window of drug responsiveness in real time. Biosensors 5:199–222
Koebe HG, Deglmann CJ, Metzger R, Hoerrlein S, Schildberg FW (2000) In vitro toxicology in hepatocyte bioreactors-extracellular acidification rate (EAR) in a target cell line indicates hepato-activated transformation of substrates. Toxicology 154:31–44
Kustermann S, Boess F, Buness A, Schmitz M, Watzele M, Weiser T et al (2013) A label-free, impedance-based real time assay to identify drug-induced toxicities and differentiate cytostatic from cytotoxic effects. Toxicol In Vitro 27:1589–1595
Lamore SD, Kamendi HW, Scott CW, Dragan YP, Peters MF (2013) Cellular impedance assays for predictive preclinical drug screening of kinase inhibitor cardiovascular toxicity. Toxicol Sci Off J Soc Toxicol 135:402–413
Lee RM, Choi H, Shin JS, Kim K, Yoo KH (2009) Distinguishing between apoptosis and necrosis using a capacitance sensor. Biosens Bioelectron 24:2586–2591
Ligler FS (2009) Perspective on optical biosensors and integrated sensor systems. Anal Chem 81:519–526
Limame R, Wouters A, Pauwels B, Fransen E, Peeters M, Lardon F et al (2012) Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays. PloS one 7:e46536
Mandel K, Seidl D, Rades D, Lehnert H, Gieseler F, Hass R et al (2013) Characterization of spontaneous and TGF-beta-induced cell motility of primary human normal and neoplastic mammary cells in vitro using novel real-time technology. PLoS One 8:e56591
Martinez-Serra J, Gutierrez A, Munoz-Capo S, Navarro-Palou M, Ros T, Amat JC et al (2014) xCELLigence system for real-time label-free monitoring of growth and viability of cell lines from hematological malignancies. OncoTargets Ther 7:985–994
Ona T, Shibata J (2010) Advanced dynamic monitoring of cellular status using label-free and non-invasive cell-based sensing technology for the prediction of anticancer drug efficacy. Anal Bioanal Chem 398:2505–2533
Roshan Moniri M, Young A, Reinheimer K, Rayat J, Dai LJ, Warnock GL (2015) Dynamic assessment of cell viability, proliferation and migration using real time cell analyzer system (RTCA). Cytotechnology 67:379–386
Solly K, Wang X, Xu X, Strulovici B, Zheng W (2004) Application of real-time cell electronic sensing (RT-CES) technology to cell-based assays. Assay Drug Dev Technol 2:363–372
Todaro MC, Oreto L, Qamar R, Paterick TE, Carerj S, Khandheria BK (2013) Cardioncology: state of the heart. Int J Cardiol 168:680–687
Torisawa YS, Takagi A, Shiku H, Yasukawa T, Matsue T (2005) A multicellular spheroid-based drug sensitivity test by scanning electrochemical microscopy. Oncol Rep 13:1107–1112
Wang T, Hu N, Cao J, Wu J, Su K, Wang P (2013) A cardiomyocyte-based biosensor for antiarrhythmic drug evaluation by simultaneously monitoring cell growth and beating. Biosens Bioelectron 49:9–13
Woolley DE, Tetlow LC, Adlam DJ, Gearey D, Eden RD (2002) Electrochemical monitoring of cell behaviour in vitro: a new technology. Biotechnol Bioeng 77:725–733
Xing JZ, Zhu L, Jackson JA, Gabos S, Sun XJ, Wang XB et al (2005) Dynamic monitoring of cytotoxicity on microelectronic sensors. Chem Res Toxicol 18:154–161
Nonclinical In Vivo Pharmacological Assessment of Oncology Therapeutics
Chapman K, Burnett J, Corvaro M, Mitchell D, Robinson S, Sangster T et al (2014) Reducing pre-clinical blood volumes for toxicokinetics: toxicologists, pathologists and bioanalysts unite. Bioanalysis 6:2965–2968
Dekker SK, van Doorn R, Kempenaar J, Gruis NA, Vermeer BJ, Ponec M (2000) Skin equivalent: an attractive model to evaluate early melanoma metastasis. Melanoma Res 10:127–140
Miller AL, Wright-Williams SL, Flecknell PA, Roughan JV (2012) A comparison of abdominal and scrotal approach methods of vasectomy and the influence of analgesic treatment in laboratory mice. Lab Anim 46:304–310
Russell W, Burch R (1959) The principles of humane experimental technique. Methuen, London
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577
Determination of Nonclinical Maximum Tolerable Dose
Guillen J (2012) FELASA guidelines and recommendations. J Am Assoc Lab Anim Sci 51:311–321
ICH (2010) International Conference on Harmonisation. S9 guidelines: nonclinical evaluation for anticancer pharmaceuticals. Fed Regist 75:10487
Russell WMS, Burch RL (1959) The principles of humane experimental technique. Methuen and Co, London
Talmadge JE, Singh RK, Fidler IJ, Raz A (2007) Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am J Pathol 170:793–804
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577
Hollow Fibre Assay
Bueno Perez L, Li J, Lantvit DD, Pan L, Ninh TN, Chai HB et al (2013) Bioactive constituents of Indigofera spicata. J Nat Prod 76:1498–1504
Hall LA, Krauthauser CM, Wexler RS, Hollingshead MG, Slee AM, Kerr JS (2000) The hollow fiber assay: continued characterization with novel approaches. Anticancer Res 20:903–911
Hollingshead MG, Alley MC, Camalier RF, Abbott BJ, Mayo JG, Malspeis L et al (1995) In vivo cultivation of tumor cells in hollow fibers. Life Sci 57:131–141
Krauthauser CM, Hall LA, Wexler RS, Slee AM, Mitra J, Enders GH et al (2001) Regulation of gene expression and cell growth in vivo by tetracycline using the hollow fiber assay. Anticancer Res 21:869–872
Mi Q, Pezzuto JM, Farnsworth NR, Wani MC, Kinghorn AD, Swanson SM (2009) Use of the in vivo hollow fiber assay in natural products anticancer drug discovery. J Nat Prod 72:573–580
Park JW, Baek NS, Lee SC, Oh SJ, Jang SH, Kim IH et al (2014) Preclinical efficacy testing for stomach and liver cancers. Cancer Res Treat 46:186–193
Shnyder SD, Cooper PA, Scally AJ, Bibby MC (2006) Reducing the cost of screening novel agents using the hollow fibre assay. Anticancer Res 26:2049–2052
Suggitt M, Cooper PA, Shnyder SD, Bibby MC (2006) The hollow fibre model–facilitating anti-cancer pre-clinical pharmacodynamics and improving animal welfare. Int J Oncol 29:1493–1499
Veiga JP, Cooper PA, Pors K, Patterson LH, Bibby MC, Shnyder SD (2011) Use of the hollow fiber assay for the evaluation of DNA damaging agents. J Pharmacol Toxicol Methods 64:226–232
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577
Sub-cutaneous Transplantation Models
Balkwill FR, Moodie EM (1984) Positive interactions between human interferon and cyclophosphamide or adriamycin in a human tumor model system. Cancer Res 44:904–908
Burgenske DM, Monsma DJ, Dylewski D, Scott SB, Sayfie AD, Kim DG et al (2014) Establishment of genetically diverse patient-derived xenografts of colorectal cancer. Am J Cancer Res 4:824–837
Damiano V, Caputo R, Garofalo S, Bianco R, Rosa R, Merola G et al (2007) TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts. Proc Natl Acad Sci U S A 104:12468–12473
Gill JH, Loadman PM, Shnyder SD, Cooper P, Atkinson JM, Ribeiro Morais G et al (2014) Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity. Mol Pharm 11:1294–1300
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Harvey TJ, Hennig IM, Shnyder SD, Cooper PA, Ingram N, Hall GD et al (2011) Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo. Cancer Gene Ther 18:773–784
Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR et al (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27:4702–4711
Nowak K, Peckham MJ, Steel GG (1978) Variation in response of xenografts of colo-rectal carcinoma to chemotherapy. Br J Cancer 37:576–584
Pors K, Loadman PM, Shnyder SD, Sutherland M, Sheldrake HM, Guino M et al (2011) Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity. Chem Commun (Camb) 47:12062–12064
Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D et al (2013) Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res Off J Am Assoc Cancer Res 19:6173–6182
Rosfjord E, Lucas J, Li G, Gerber HP (2014) Advances in patient-derived tumor xenografts: from target identification to predicting clinical response rates in oncology. Biochem Pharmacol 91:135–143
Shnyder SD, Cooper PA, Gyselinck N, Hill BT, Double JA, Bibby MC (2003) Vinflunine potentiates the activity of cisplatin but not 5-fluorouracil in a transplantable murine adenocarcinoma model. Anticancer Res 23:4815–4820
Shnyder SD, Cooper PA, Millington NJ, Pettit GR, Bibby MC (2007) Auristatin PYE, a novel synthetic derivative of dolastatin 10, is highly effective in human colon tumour models. Int J Oncol 31:353–360
Siolas D, Hannon GJ (2013) Patient-derived tumor xenografts: transforming clinical samples into mouse models. Cancer Res 73:5315–5319
Suggitt M, Bibby MC (2005) 50 years of preclinical anticancer drug screening: empirical to target-driven approaches. Clin Cancer Res Off J Am Assoc Cancer Res 11:971–981
Talmadge JE, Singh RK, Fidler IJ, Raz A (2007) Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am J Pathol 170:793–804
Tomlinson DC, Lamont FR, Shnyder SD, Knowles MA (2009) Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancer. Cancer Res 69:4613–4620
Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577
Creation of Orthotopic Cancer Models
Jager W, Moskalev I, Janssen C, Hayashi T, Awrey S, Gust KM et al (2013) Ultrasound-guided intramural inoculation of orthotopic bladder cancer xenografts: a novel high-precision approach. PLoS One 8:e59536
Kozlowski JM, Fidler IJ, Campbell D, Xu ZL, Kaighn ME, Hart IR (1984) Metastatic behavior of human tumor cell lines grown in the nude mouse. Cancer Res 44:3522–3529
Legrand N, Weijer K, Spits H (2006) Experimental models to study development and function of the human immune system in vivo. J Immunol 176:2053–2058
Pavese J, Ogden IM, Bergan RC (2013) An orthotopic murine model of human prostate cancer metastasis. J Vis Exp JoVE:e50873. doi:10.3791/50873
Rosfjord E, Lucas J, Li G, Gerber HP (2014) Advances in patient-derived tumor xenografts: from target identification to predicting clinical response rates in oncology. Biochem Pharmacol 91:135–143
Sicklick JK, Leonard SY, Babicky ML, Tang CM, Mose ES, French RP et al (2014) Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor. J Transl Med 12:41
Talmadge JE, Singh RK, Fidler IJ, Raz A (2007) Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am J Pathol 170:793–804
Teitz T, Stanke JJ, Federico S, Bradley CL, Brennan R, Zhang J et al (2011) Preclinical models for neuroblastoma: establishing a baseline for treatment. PLoS One 6:e19133
Site-Specific Cancer Models
Eswaraka J, Giddabasappa A, Han G, Lalwani K, Eisele K, Feng Z et al (2014) Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer. BMC Cancer 14:742
Fraedrich K, Schrader J, Ittrich H, Keller G, Gontarewicz A, Matzat V et al (2012) Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model. Clin Cancer Res 18:4621–4632
Grabowski P, Schrader J, Wagner J, Horsch D, Arnold R, Arnold CN et al (2008) Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors. Clin Cancer Res 14:7378–7384
Liang Z, Zhan W, Zhu A, Yoon Y, Lin S, Sasaki M et al (2012) Development of a unique small molecule modulator of CXCR4. PLoS One 7:e34038
Nakayama A, Takagi S, Yusa T, Yaguchi M, Hayashi A, Tamura T et al (2013) Antitumor activity of TAK-285, an investigational, non-Pgp substrate HER2/EGFR kinase inhibitor, in cultured tumor cells, mouse and rat xenograft tumors, and in an HER2-positive brain metastasis model. J Cancer 4:557–565
Models of Spontaneous Tumours
Das Thakur M, Pryer NK, Singh M (2014) Mouse tumour models to guide drug development and identify resistance mechanisms. J Pathol 232:103–111
Dragani TA, Peissel B, Zanesi N, Aloisi A, Dai Y, Kato M et al (2000) Mapping of melanoma modifier loci in RET transgenic mice. Jpn J Cancer Res 91:1142–1147
Gatti L, Sevko A, De Cesare M, Arrighetti N, Manenti G, Ciusani E et al (2014) Histone deacetylase inhibitor-temozolomide co-treatment inhibits melanoma growth through suppression of Chemokine (C-C motif) ligand 2-driven signals. Oncotarget 5:4516–4528
Heyer J, Kwong LN, Lowe SW, Chin L (2010) Non-germline genetically engineered mouse models for translational cancer research. Nat Rev Cancer 10:470–480
Levin I (1912) Tumor inoculation into organs and the analogy between human cancer and the tumors of white mice and white rats. J Exp Med 16:155–164
Talmadge JE, Singh RK, Fidler IJ, Raz A (2007) Murine models to evaluate novel and conventional therapeutic strategies for cancer. Am J Pathol 170:793–804
Development of Haematopoietic Tumour Models
Bosma GC, Custer RP, Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301:527–530
Chiang MY, Xu L, Shestova O, Histen G, L’Heureux S, Romany C et al (2008) Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J Clin Invest 118:3181–3194
Cocco C, Canale S, Frasson C, Di Carlo E, Ognio E, Ribatti D et al (2010) Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells. Blood 116:3887–3898
Findley HW Jr, Cooper MD, Kim TH, Alvarado C, Ragab AH (1982) Two new acute lymphoblastic leukemia cell lines with early B-cell phenotypes. Blood 60:1305–1309
Greiner DL, Shultz LD, Yates J, Appel MC, Perdrizet G, Hesselton RM et al (1995) Improved engraftment of human spleen cells in NOD/LtSz-scid/scid mice as compared with C.B-17-scid/scid mice. Am J Pathol 146:888–902
Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K et al (2002) NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100:3175–3182
Jacoby E, Chien CD, Fry TJ (2014) Murine models of acute leukemia: important tools in current pediatric leukemia research. Front Oncol 4:95
Kindler T, Cornejo MG, Scholl C, Liu J, Leeman DS, Haydu JE et al (2008) K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors. Blood 112:3373–3382
Li S, Ilaria RL Jr, Million RP, Daley GQ, Van Etten RA (1999) The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med 189:1399–1412
Mantripragada K, Reagan JL, Quesenberry PJ, Fast LD (2014) Advances in cellular therapy for the treatment of leukemia. Discov Med 17:15–24
Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7:118–130
Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD et al (2010) Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 17:427–442
Non-invasive Evaluation of Cancer Models
Agollah GD, Wu G, Sevick-Muraca EM, Kwon S (2014) In vivo lymphatic imaging of a human inflammatory breast cancer model. J Cancer 5:774–783
Badea CT, Athreya KK, Espinosa G, Clark D, Ghafoori AP, Li Y et al (2012) Computed tomography imaging of primary lung cancer in mice using a liposomal-iodinated contrast agent. PLoS One 7:e34496
Beckmann N, Kneuer R, Gremlich HU, Karmouty-Quintana H, Ble FX, Muller M (2007) In vivo mouse imaging and spectroscopy in drug discovery. NMR Biomed 20:154–185
Chai MG, Kim-Fuchs C, Angst E, Sloan EK (2013) Bioluminescent orthotopic model of pancreatic cancer progression. J Vis Exp JoVE. doi:10.3791/50395
Couture F, Levesque C, Dumulon-Perreault V, Ait-Mohand S, D’Anjou F, Day R et al (2014) PACE4-based molecular targeting of prostate cancer using an engineered (6)(4)Cu-radiolabeled peptide inhibitor. Neoplasia 16:634–643
Daudigeos-Dubus E, Le Dret L, Rouffiac V, Bawa O, Leguerney I, Opolon P et al (2014) Establishment and characterization of new orthotopic and metastatic neuroblastoma models. In Vivo 28:425–434
Downey CM, Aghaei M, Schwendener RA, Jirik FR (2014) DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2′3′-cGAMP, induces M2 macrophage repolarization. PLoS One 9:e99988
Ferrandis E, Da Silva J, Riou G, Benard I (1994) Coactivation of the MDR1 and MYCN genes in human neuroblastoma cells during the metastatic process in the nude mouse. Cancer Res 54:2256–2261
Fushiki H, Kanoh-Azuma T, Katoh M, Kawabata K, Jiang J, Tsuchiya N et al (2009) Quantification of mouse pulmonary cancer models by microcomputed tomography imaging. Cancer Sci 100:1544–1549
Garcia C, Dubois LG, Xavier AL, Geraldo LH, da Fonseca AC, Correia AH et al (2014) The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model. BMC Cancer 14:923
Ingram N, Macnab SA, Marston G, Scott N, Carr IM, Markham AF et al (2013) The use of high-frequency ultrasound imaging and biofluorescence for in vivo evaluation of gene therapy vectors. BMC Med Imaging 13:35
Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander AS et al (2014) Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS One 9:e85311
Larimer BM, Deutscher SL (2014) Development of a peptide by phage display for SPECT imaging of resistance-susceptible breast cancer. Am J Nucl Med Mol Imaging 4:435–447
Li D, Liu S, Liu R, Park R, Hughes L, Krasnoperov V et al (2013) Targeting the EphB4 receptor for cancer diagnosis and therapy monitoring. Mol Pharm 10:329–336
Ma J, Xing LX, Shen M, Li F, Zhu MJ, Jin LF et al (2015) Ultrasound contrast-enhanced imaging and in vitro antitumor effect of paclitaxel-poly(lactic-co-glycolic acid)-monomethoxypoly (ethylene glycol) nanocapsules with ultrasound-targeted microbubble destruction. Mol Med Rep 11:2413–2420
Mittra ES, Fan-Minogue H, Lin FI, Karamchandani J, Sriram V, Han M et al (2013) Preclinical efficacy of the anti-hepatocyte growth factor antibody ficlatuzumab in a mouse brain orthotopic glioma model evaluated by bioluminescence, PET, and MRI. Clin Cancer Res 19:5711–5721
O’Farrell AC, Shnyder SD, Marston G, Coletta PL, Gill JH (2013) Non-invasive molecular imaging for preclinical cancer therapeutic development. Br J Pharmacol 169:719–735
Qin H, Zhang MR, Xie L, Hou Y, Hua Z, Hu M et al (2015) PET imaging of apoptosis in tumor-bearing mice and rabbits after paclitaxel treatment with (18)F(-)Labeled recombinant human His10-annexin V. Am J Nucl Med Mol Imaging 5:27–37
Thorsen F, Fite B, Mahakian LM, Seo JW, Qin S, Harrison V et al (2013) Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases. J Control Release 172:812–822
Whisenant JG, Sorace AG, McIntyre JO, Kang H, Sanchez V, Loveless ME et al (2014) Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts. Transl Oncol 7:768–779
Regulatory Guidance for Clinical Development of Oncology Therapeutics
Food and Drug Administration HHS (2012) International Conference on Harmonisation; addendum to International Conference on Harmonisation Guidance on S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals; availability. Notice. Fed Regist 77:29665–29666
ICH (2010) International Conference on Harmonisation. S9 Guidelines: Nonclinical evaluation for Anticancer Pharmaceuticals. Federal Register 75:10487
Lewis RM, Cavagnaro J (2010) The application of ICH S6 to the preclinical safety evaluation of plasma derivative therapeutic products. Biol J Int Assoc Biol Stand 38:494–500
Newell DR (2005) How to develop a successful cancer drug–molecules to medicines or targets to treatments? Eur J Cancer 41:676–682
Ocana A, Pandiella A, Siu LL, Tannock IF (2011) Preclinical development of molecular-targeted agents for cancer. Nat Rev Clin Oncol 8:200–209
Ponce R (2011) ICH S9: developing anticancer drugs, one year later. Toxicol Pathol 39:913–915
Rosenfeldt H, Kropp T, Benson K, Ricci MS, McGuinn WD, Verbois SL (2010) Regulatory aspects of oncology drug safety evaluation: past practice, current issues, and the challenge of new drugs. Toxicol Appl Pharmacol 243:125–133
Senderowicz AM (2010) Information needed to conduct first-in-human oncology trials in the United States: a view from a former FDA medical reviewer. Clin Cancer Res Off J Am Assoc Cancer Res 16:1719–1725
Walker I, Newell H (2009) Do molecularly targeted agents in oncology have reduced attrition rates? Nat Rev 8:15–16
Westhouse RA (2010) Safety assessment considerations and strategies for targeted small molecule cancer therapeutics in drug discovery. Toxicol Pathol 38:165–168
Wittenburg LA, Gustafson DL (2011) Optimizing preclinical study design in oncology research. Chem Biol Interact 190:73–78
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer-Verlag Berlin Heidelberg
About this entry
Cite this entry
Gill, J.H., Shnyder, S.D. (2015). Oncology Activity. In: Hock, F. (eds) Drug Discovery and Evaluation: Pharmacological Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27728-3_113-1
Download citation
DOI: https://doi.org/10.1007/978-3-642-27728-3_113-1
Received:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Online ISBN: 978-3-642-27728-3
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences