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Cellular pharmacology studies of anticancer agents: recommendations from the EORTC-PAMM group

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Abstract

An increasing number of manuscripts focus on the in vitro evaluation of established and novel anti-tumor agents in experimental models. Whilst the design of such in vitro assays is inherently flexible, some of these studies lack the minimum information necessary to critically evaluate their relevance or have been carried out under unsuitable conditions. The use of appropriate and robust methods and experimental design has important implications for generating results that are reliable, relevant, and reproducible. The Pharmacology and Molecular Mechanisms (PAMM) group of the European Organization for Research and Treatment of Cancer (EORTC) is the largest group of academic scientists working on drug development and bundle decades of expertise in this field. This position paper addresses all researchers with an interest in the preclinical and cellular pharmacology of anti-tumor agents and aims at generating basic recommendations for the correct use of compounds to be tested for anti-tumor activity using a range of preclinical cellular models of cancer.

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References

  1. Tajeddine N, Galluzzi L, Kepp O, Hangen E, Morselli E, Senovilla L, Araujo N, Pinna G, Larochette N, Zamzami N, Modjtahedi N, Harel-Bellan A, Kroemer G (2008) Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death. Oncogene 27:4221–4232

    Article  CAS  PubMed  Google Scholar 

  2. Mantovani F, Piazza S, Gostissa M, Strano S, Zacchi P, Mantovani R, Blandino G, Del Sal G (2004) Pin1 links the activities of c-Abl and p300 in regulating p73 function. Mol Cell 14:625–636

    Article  CAS  PubMed  Google Scholar 

  3. Hendriks HR, Govaerts AS, Fichtner I, Burtles S, Westwell AD, Peters GJ (2017) Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative. Br J Cancer 117:195–202

    Article  PubMed  Google Scholar 

  4. Righetti SC, Perego P, Carenini N, Zunino F (2008) Cooperation between p53 and p73 in cisplatin-induced apoptosis in ovarian carcinoma cells. Cancer Lett 263:140–144

    Article  CAS  PubMed  Google Scholar 

  5. Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C (2006) Clonogenic assay of cells in vitro. Nat Protoc 1:2315–2319

    Article  CAS  PubMed  Google Scholar 

  6. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48:589–601

    CAS  PubMed  Google Scholar 

  7. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112

    Article  CAS  PubMed  Google Scholar 

  8. Kahn J, Tofilon PJ, Camphausen K (2012) Preclinical models in radiation oncology. Radiat Oncol 7:223–717:X-7-223

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741

    Article  CAS  PubMed  Google Scholar 

  10. Rossi C, Gasparini G, Canobbio L, Galligioni E, Volpe R, Candiani E, Toffoli G, D’Incalci M (1987) Doxorubicin distribution in human breast cancer. Cancer Treat Rep 71:1221–1226

    CAS  PubMed  Google Scholar 

  11. Minchinton AI, Tannock IF (2006) Drug penetration in solid tumours. Nat Rev Cancer 6:583–592

    Article  CAS  PubMed  Google Scholar 

  12. Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276

    Article  CAS  PubMed  Google Scholar 

  13. Lanvers C, Hempel G, Blaschke G, Boos J (1998) Chemically induced isomerization and differential uptake modulate retinoic acid disposition in HL-60 cells. FASEB J 12:1627–1633

    Article  CAS  PubMed  Google Scholar 

  14. Serova M, Tijeras-Raballand A, Dos Santos C, Martinet M, Neuzillet C, Lopez A, Mitchell DC, Bryan BA, Gapihan G, Janin A, Bousquet G, Riveiro ME, Bieche I, Faivre S, Raymond E, de Gramont A (2016) Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib. Oncotarget 7:38467–38486

    Article  PubMed  PubMed Central  Google Scholar 

  15. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, Griffioen AW, Assaraf YG, Pili R, Peters GJ, Verheul HM (2011) Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res 17:7337–7346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gotink KJ, Broxterman HJ, Honeywell RJ, Dekker H, de Haas RR, Miles KM, Adelaiye R, Griffioen AW, Peters GJ, Pili R, Verheul HM (2014) Acquired tumor cell resistance to sunitinib causes resistance in a HT-29 human colon cancer xenograft mouse model without affecting sunitinib biodistribution or the tumor microvasculature. Oncoscience 1:844–853

    Article  PubMed  PubMed Central  Google Scholar 

  17. Peters GJ, Lankelma J, Kok RM, Noordhuis P, van Groeningen CJ, van der Wilt CL, Meyer S, Pinedo HM (1993) Prolonged retention of high concentrations of 5-fluorouracil in human and murine tumors as compared with plasma. Cancer Chemother Pharmacol 31:269–276

    Article  CAS  PubMed  Google Scholar 

  18. Da Silva CG, Honeywell RJ, Dekker H, Peters GJ (2015) Physicochemical properties of novel protein kinase inhibitors in relation to their substrate specificity for drug transporters. Expert Opin Drug Metab Toxicol 11:703–717

    Article  PubMed  Google Scholar 

  19. van der Veldt AA, Smit EF, Lammertsma AA (2013) Positron emission tomography as a method for measuring drug delivery to tumors in vivo: the example of [(11)C]docetaxel. Front Oncol 3:208

    PubMed  PubMed Central  Google Scholar 

  20. Bahce I, Smit EF, Lubberink M, van der Veldt AA, Yaqub M, Windhorst AD, Schuit RC, Thunnissen E, Heideman DA, Postmus PE, Lammertsma AA, Hendrikse NH (2013) Development of [(11)C]erlotinib positron emission tomography for in vivo evaluation of EGF receptor mutational status. Clin Cancer Res 19:183–193

    Article  CAS  PubMed  Google Scholar 

  21. Qazzaz ME, Raja VJ, Lim KH, Kam TS, Lee JB, Gershkovich P, Bradshaw TD (2016) In vitro anticancer properties and biological evaluation of novel natural alkaloid jerantinine B. Cancer Lett 370:185–197

    Article  CAS  PubMed  Google Scholar 

  22. Stone EL, Citossi F, Singh R, Kaur B, Gaskell M, Farmer PB, Monks A, Hose C, Stevens MF, Leong CO, Stocks M, Kellam B, Marlow M, Bradshaw TD (2015) Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery. Bioorg Med Chem 23:6891–6899

    Article  CAS  PubMed  Google Scholar 

  23. Berndtsson M, Hagg M, Panaretakis T, Havelka AM, Shoshan MC, Linder S (2007) Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA. Int J Cancer 120:175–180

    Article  CAS  PubMed  Google Scholar 

  24. Akpinar B, Bracht EV, Reijnders D, Safarikova B, Jelinkova I, Grandien A, Vaculova AH, Zhivotovsky B, Olsson M (2015) 5-Fluorouracil-induced RNA stress engages a TRAIL-DISC-dependent apoptosis axis facilitated by p53. Oncotarget 6:43679–43697

    Article  PubMed  PubMed Central  Google Scholar 

  25. van Groeningen CJ, Pinedo HM, Heddes J, Kok RM, de Jong AP, Wattel E, Peters GJ, Lankelma J (1988) Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule. Cancer Res 48:6956–6961

    PubMed  Google Scholar 

  26. Himmelstein KJ, Patton TF, Belt RJ, Taylor S, Repta AJ, Sternson LA (1981) Clinical kinetics on intact cisplatin and some related species. Clin Pharmacol Ther 29:658–664

    Article  CAS  PubMed  Google Scholar 

  27. van Moorsel CJ, Kroep JR, Pinedo HM, Veerman G, Voorn DA, Postmus PE, Vermorken JB, van Groeningen CJ, van der Vijgh WJ, Peters GJ (1999) Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Ann Oncol 10:441–448

    Article  PubMed  Google Scholar 

  28. Vanarkotte J, Peters G, Pizao P, Keepers Y, Giaccone G (1994) In-vitro schedule-dependency of eo9 and miltefosine in comparison to standard drugs in colon-cancer cells. Int J Oncol 4:709–715

    CAS  PubMed  Google Scholar 

  29. Lee LF, Li G, Templeton DJ, Ting JP (1998) Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2-terminal kinase (JNK/SAPK). J Biol Chem 273:28253–28260

    Article  CAS  PubMed  Google Scholar 

  30. Borst P, Borst J, Smets LA (2001) Does resistance to apoptosis affect clinical response to antitumor drugs? Drug Resist Updat 4:129–131

    Article  CAS  PubMed  Google Scholar 

  31. Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5:231–237

    Article  CAS  PubMed  Google Scholar 

  32. Havelka AM, Berndtsson M, Olofsson MH, Shoshan MC, Linder S (2007) Mechanisms of action of DNA-damaging anticancer drugs in treatment of carcinomas: is acute apoptosis an “off-target” effect? Mini Rev Med Chem 7:1035–1039

    Article  CAS  PubMed  Google Scholar 

  33. Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 18:1272–1282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Borst P, Rottenberg S (2004) Cancer cell death by programmed necrosis? Drug Resist Updat 7:321–324

    Article  CAS  PubMed  Google Scholar 

  35. Gonzalez VM, Fuertes MA, Alonso C, Perez JM (2001) Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol 59:657–663

    Article  CAS  PubMed  Google Scholar 

  36. Ivanov AI, Christodoulou J, Parkinson JA, Barnham KJ, Tucker A, Woodrow J, Sadler PJ (1998) Cisplatin binding sites on human albumin. J Biol Chem 273:14721–14730

    Article  CAS  PubMed  Google Scholar 

  37. Faulkner AD, Kaner RA, Abdallah QM, Clarkson G, Fox DJ, Gurnani P, Howson SE, Phillips RM, Roper DI, Simpson DH, Scott P (2014) Asymmetric triplex metallohelices with high and selective activity against cancer cells. Nat Chem 6:797–803

    Article  CAS  PubMed  Google Scholar 

  38. Kaner RA, Allison SJ, Faulkner AD, Phillips RM, Roper DI, Shepherd SL, Simpson DH, Waterfield NR, Scott P (2016) Anticancer metallohelices: nanomolar potency and high selectivity. Chem Sci 7:951–958

    Article  CAS  PubMed  Google Scholar 

  39. Hall MD, Telma KA, Chang KE, Lee TD, Madigan JP, Lloyd JR, Goldlust IS, Hoeschele JD, Gottesman MM (2014) Say no to DMSO: dimethylsulfoxide inactivates cisplatin, carboplatin, and other platinum complexes. Cancer Res 74:3913–3922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sundquist WI, Lippard SJ, Stollar BD (1987) Monoclonal antibodies to DNA modified with cis- or trans-diamminedichloroplatinum(II). Proc Natl Acad Sci USA 84:8225–8229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fischer SJ, Benson LM, Fauq A, Naylor S, Windebank AJ (2008) Cisplatin and dimethyl sulfoxide react to form an adducted compound with reduced cytotoxicity and neurotoxicity. Neurotoxicology 29:444–452

    Article  CAS  PubMed  Google Scholar 

  42. Zheng H, Fink D, Howell SB (1997) Pharmacological basis for a novel therapeutic strategy based on the use of aquated cisplatin. Clin Cancer Res 3:1157–1165

    CAS  PubMed  Google Scholar 

  43. Honeywell RJ, Fatmawati C, Buddha M, Hitzerd S, Kathman I, Peters GJ (2015) Adaptation of a human gut epithelial model in relation to the assessment of clinical pharmacokinetic parameters for selected tyrosine kinase inhibitors. ADMET DMPK 3:51–67

    Article  Google Scholar 

  44. Wagner A, Hempel G, Gumbinger HG, Jurgens H, Boos J (1999) Pharmacokinetics of anticancer drugs in vitro. Adv Exp Med Biol 457:397–407

    Article  CAS  PubMed  Google Scholar 

  45. Jacobson PA, Green K, Birnbaum A, Remmel RP (2002) Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA. Cancer Chemother Pharmacol 49:461–467

    Article  CAS  PubMed  Google Scholar 

  46. Phillips RM, Bibby MC, Double JA (1988) Experimental correlations of in vitro drug sensitivity with in vivo responses to ThioTEPA in a panel of murine colon tumours. Cancer Chemother Pharmacol 21:168–172

    Article  CAS  PubMed  Google Scholar 

  47. Xu Y, Villalona-Calero MA (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol 13:1841–1851

    Article  CAS  PubMed  Google Scholar 

  48. Perego P, Robert J (2016) Oxaliplatin in the era of personalized medicine: from mechanistic studies to clinical efficacy. Cancer Chemother Pharmacol 77:5–18

    Article  CAS  PubMed  Google Scholar 

  49. Emadi A, Jones RJ, Brodsky RA (2009) Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 6:638–647

    Article  CAS  PubMed  Google Scholar 

  50. Ahlmann M, Hempel G (2016) The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol 78:661–671

    Article  CAS  PubMed  Google Scholar 

  51. Kolosenko I, Avnet S, Baldini N, Viklund J, De Milito A (2017) Therapeutic implications of tumor interstitial acidification. Semin Cancer Biol 43:119–133

    Article  CAS  PubMed  Google Scholar 

  52. Phillips RM (2016) Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs. Cancer Chemother Pharmacol 77:441–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gallagher FA, Kettunen MI, Day SE, Hu DE, Ardenkjaer-Larsen JH, Zandt R, Jensen PR, Karlsson M, Golman K, Lerche MH, Brindle KM (2008) Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453:940–943

    Article  CAS  PubMed  Google Scholar 

  54. Hashim AI, Zhang X, Wojtkowiak JW, Martinez GV, Gillies RJ (2011) Imaging pH and metastasis. NMR Biomed 24:582–591

    PubMed  PubMed Central  Google Scholar 

  55. Oudin MJ, Weaver VM (2016) Physical and chemical gradients in the tumor microenvironment regulate tumor cell invasion, migration, and metastasis. Cold Spring Harb Symp Quant Biol 81:189–205

    Article  PubMed  Google Scholar 

  56. Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, Baba Y (2013) Acidic extracellular microenvironment and cancer. Cancer Cell Int 13:89–2867-13-89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Swietach P, Vaughan-Jones RD, Harris AL, Hulikova A (2014) The chemistry, physiology and pathology of pH in cancer. Philos Trans R Soc Lond B Biol Sci 369:20130099

    Article  PubMed  PubMed Central  Google Scholar 

  58. Larsen AK, Escargueil AE, Skladanowski A (2000) Resistance mechanisms associated with altered intracellular distribution of anticancer agents. Pharmacol Ther 85:217–229

    Article  CAS  PubMed  Google Scholar 

  59. Valko KL, Teague SP, Pidgeon C (2017) In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery. ADMET DMPK 5:14–38

    Article  Google Scholar 

  60. Almeida JL, Cole KD, Plant AL (2016) Standards for cell line authentication and beyond. PLoS Biol 14:e1002476

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hunter FW, Wouters BG, Wilson WR (2016) Hypoxia-activated prodrugs: paths forward in the era of personalised medicine. Br J Cancer 114:1071–1077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Walsby E, Pratt G, Shao H, Abbas AY, Fischer PM, Bradshaw TD, Brennan P, Fegan C, Wang S, Pepper C (2014) A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. Oncotarget 5:375–385

    Article  PubMed  Google Scholar 

  63. Clevers H (2005) Stem cells, asymmetric division and cancer. Nat Genet 37:1027–1028

    Article  CAS  PubMed  Google Scholar 

  64. Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284

    Article  CAS  PubMed  Google Scholar 

  65. Dalerba P, Clarke MF (2007) Cancer stem cells and tumor metastasis: first steps into uncharted territory. Cell Stem Cell 1:241–242

    Article  CAS  PubMed  Google Scholar 

  66. Freshney RI (2016) Culture of animal cells: a manual of basic technique and specialized applications, 7th edn, Wiley-Blackwell

  67. Collins L, Franzblau SG (1997) Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother 41:1004–1009

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Jabbar SA, Twentyman PR, Watson JV (1989) The MTT assay underestimates the growth inhibitory effects of interferons. Br J Cancer 60:523–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. van Moorsel CJ, Bergman AM, Veerman G, Voorn DA, Ruiz van Haperen VW, Kroep JR, Pinedo HM, Peters GJ (2000) Differential effects of gemcitabine on ribonucleotide pools of twenty-one solid tumour and leukaemia cell lines. Biochim Biophys Acta 1474:5–12

    Article  PubMed  Google Scholar 

  70. Fayad W, Brnjic S, Berglind D, Blixt S, Shoshan MC, Berndtsson M, Olofsson MH, Linder S (2009) Restriction of cisplatin induction of acute apoptosis to a subpopulation of cells in a three-dimensional carcinoma culture model. Int J Cancer 125:2450–2455

    Article  CAS  PubMed  Google Scholar 

  71. Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK (2003) Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol Bioeng 83:173–180

    Article  CAS  PubMed  Google Scholar 

  72. Padron JM, van der Wilt CL, Smid K, Smitskamp-Wilms E, Backus HH, Pizao PE, Giaccone G, Peters GJ (2000) The multilayered postconfluent cell culture as a model for drug screening. Crit Rev Oncol Hematol 36:141–157

    Article  CAS  PubMed  Google Scholar 

  73. Sutherland RM, Eddy HA, Bareham B, Reich K, Vanantwerp D (1979) Resistance to adriamycin in multicellular spheroids. Int J Radiat Oncol Biol Phys 5:1225–1230

    Article  CAS  PubMed  Google Scholar 

  74. Olive PL, Durand RE (1994) Drug and radiation resistance in spheroids: cell contact and kinetics. Cancer Metastasis Rev 13:121–138

    Article  CAS  PubMed  Google Scholar 

  75. Frankel A, Buckman R, Kerbel RS (1997) Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids. Cancer Res 57:2388–2393

    CAS  PubMed  Google Scholar 

  76. D’Arcangelo M, Todaro M, Salvini J, Benfante A, Colorito ML, D’Incecco A, Landi L, Apuzzo T, Rossi E, Sani S, Stassi G, Cappuzzo F (2015) Cancer stem cells sensitivity assay (STELLA) in patients with advanced lung and colorectal cancer: a feasibility study. PLoS One 10:e0125037

    Article  PubMed  PubMed Central  Google Scholar 

  77. Beretta GL, De Cesare M, Albano L, Magnifico A, Carenini N, Corna E, Perego P, Gatti L (2016) Targeting peptidyl-prolyl isomerase pin1 to inhibit tumor cell aggressiveness. Tumori 102:144–149

    Article  PubMed  Google Scholar 

  78. Drost J, Clevers H (2017) Translational applications of adult stem cell-derived organoids. Development 144:968–975

    Article  CAS  PubMed  Google Scholar 

  79. Phillips RM, Loadman PM, Cronin BP (1998) Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours. Br J Cancer 77:2112–2119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hicks KO, Pruijn FB, Sturman JR, Denny WA, Wilson WR (2003) Multicellular resistance to tirapazamine is due to restricted extravascular transport: a pharmacokinetic/pharmacodynamic study in HT29 multicellular layer cultures. Cancer Res 63:5970–5977

    CAS  PubMed  Google Scholar 

  81. Foehrenbacher A, Secomb TW, Wilson WR, Hicks KO (2013) Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling. Front Oncol 3:314

    PubMed  PubMed Central  Google Scholar 

  82. Groh CM, Hubbard ME, Jones PF, Loadman PM, Periasamy N, Sleeman BD, Smye SW, Twelves CJ, Phillips RM (2014) Mathematical and computational models of drug transport in tumours. J R Soc Interface 11:20131173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chou TC (2010) Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Res 70:440–446

    Article  CAS  PubMed  Google Scholar 

  84. Bijnsdorp IV, Giovannetti E, Peters GJ (2011) Analysis of drug interactions. Methods Mol Biol 731:421–434

    Article  CAS  PubMed  Google Scholar 

  85. Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP (2000) Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol Ther 87:227–253

    Article  CAS  PubMed  Google Scholar 

  86. Kern DH, Morgan CR, Hildebrand-Zanki SU (1988) In vitro pharmacodynamics of 1-beta-d-arabinofuranosylcytosine: synergy of antitumor activity with cis-diamminedichloroplatinum(II). Cancer Res 48:117–121

    CAS  PubMed  Google Scholar 

  87. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  CAS  PubMed  Google Scholar 

  88. Corsello SM, Bittker JA, Liu Z, Gould J, McCarren P, Hirschman JE, Johnston SE, Vrcic A, Wong B, Khan M, Asiedu J, Narayan R, Mader CC, Subramanian A, Golub TR (2017) The drug repurposing hub: a next-generation drug library and information resource. Nat Med 23:405–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  CAS  PubMed  Google Scholar 

  90. Eastman A (2017) Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays. Oncotarget 8:8854–8866

    Article  PubMed  Google Scholar 

  91. Baker M (2016) Reproducibility: respect your cells! Nature 537:433–435

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

PP is in part supported by the Associazione Italiana per la Ricerca sul Cancro, Milan (AIRC-IG rif 15333). This review article was prepared on behalf of the EORTC-PAMM group.

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Correspondence to Paola Perego.

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Perego, P., Hempel, G., Linder, S. et al. Cellular pharmacology studies of anticancer agents: recommendations from the EORTC-PAMM group. Cancer Chemother Pharmacol 81, 427–441 (2018). https://doi.org/10.1007/s00280-017-3502-7

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