Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2012

01-03-2012 | Original Article

In vitro evaluation of clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing normal tissues

Authors: Caroline Haglund, Anna Åleskog, Peter Nygren, Joachim Gullbo, Martin Höglund, Malin Wickström, Rolf Larsson, Elin Lindhagen

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2012

Login to get access

Abstract

Purpose

The aim of this study was to evaluate a phenotypic cell panel with tumor cells from various patients and normal cells for preclinical profiles of antitumor efficacy and toxicity of anticancer drugs.

Methods

The antitumor activity of fourteen anticancer drugs was tested in over one hundred tumor samples from patients with solid or hematological malignancies. Drug activity against four normal cell types was used for the assessment of normal tissue toxicity. In vitro activity of the drugs was compared with indications approved by the Food and Drug Administration and established adverse event profiles.

Results

In general, in vitro drug activity in tumor cells from patients reflected known clinical activity of the drugs investigated. For example, the clinical activity of imatinib in chronic myeloid leukemia was clearly detected in the tumor panel. Further, and in accordance with clinical use, cisplatin and bortezomib showed high activity in ovarian cancer and myeloma samples, respectively. The normal cell models roughly reflected known clinical toxicity profiles and were able to detect differences in therapeutic index, e.g., between targeted drugs and classical cytotoxic agents. For example, the high tolerability of imatinib and the well-known renal toxicity of cisplatin were demonstrated.

Conclusions

In preclinical drug development, primary tumor cells from patients can be used for the prediction of cancer diagnosis–specific activity and may aid in the selection of diagnoses for clinical trials. By using tumor and toxicity panels together, information about therapeutic index may be derived, which may be useful when choosing among drug candidates with similar tumor effects.
Appendix
Available only for authorised users
Literature
1.
Damia G, D’Incalci M (2009) Contemporary pre-clinical development of anticancer agents–what are the optimal preclinical models? Eur J Cancer 45:2768–2781PubMedCrossRef
2.
Voskoglou-Nomikos T, Pater JL, Seymour L (2003) Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin Cancer Res 9:4227–4239PubMed
3.
Peterson JK, Houghton PJ (2004) Integrating pharmacology and in vivo cancer models in preclinical and clinical drug development. Eur J Cancer 40:837–844PubMedCrossRef
4.
Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM et al (2001) Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 84:1424–1431PubMedCrossRef
5.
Sharma SV, Haber DA, Settleman J (2010) Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nature reviews 10:241–253PubMedCrossRef
6.
Li W, Lam M, Choy D, Birkeland A, Sullivan ME et al (2006) Human primary renal cells as a model for toxicity assessment of chemo-therapeutic drugs. Toxicol In Vitro 20:669–676PubMedCrossRef
7.
Li AP, Bode C, Sakai Y (2004) A novel in vitro system, the integrated discrete multiple organ cell culture (IdMOC) system, for the evaluation of human drug toxicity: comparative cytotoxicity of tamoxifen towards normal human cells from five major organs and MCF-7 adenocarcinoma breast cancer cells. Chem Biol Interact 150:129–136PubMedCrossRef
8.
Bosanquet AG, Bell PB (2004) Ex vivo therapeutic index by drug sensitivity assay using fresh human normal and tumor cells. J Exp Ther Oncol 4:145–154PubMed
9.
Li W, Lam MS, Birkeland A, Riffel A, Montana L et al (2006) Cell-based assays for profiling activity and safety properties of cancer drugs. J Pharmacol Toxicol Methods 54:313–319PubMedCrossRef
10.
Fridborg H, Jonsson E, Nygren P, Larsson R (1999) Relationship between diagnosis-specific activity of cytotoxic drugs in fresh human tumour cells ex vivo and in the clinic. Eur J Cancer 35:424–432PubMedCrossRef
11.
Lindhagen E, Nygren P, Larsson R (2008) The fluorometric microculture cytotoxicity assay. Nat Protoc 3:1364–1369PubMedCrossRef
12.
Haglund C, Aleskog A, Hakansson LD, Hoglund M, Jacobsson S et al (2010) The FMCA-GM assays, high throughput non-clonogenic alternatives to CFU-GM in preclinical hematotoxicity testing. Toxicol Lett 194:102–107PubMedCrossRef
13.
Larsson R, Kristensen J, Sandberg C, Nygren P (1992) Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia, using a fluorometric microculture cytotoxicity assay (FMCA). Int J Cancer 50:177–185PubMedCrossRef
14.
15.
Ramström H (ed) (2009) Läkemedelsboken. 17 edn. Apoteket AB, Stockholm
16.
FASS (ed) (2009) FASS. The Swedish Drug Compendium, Läkemedelsindustriförenningen AB
17.
18.
Wolf D, Rumpold H (2009) A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours. Drug Saf 32:1001–1015PubMedCrossRef
19.
Sanz M, Burnett A, Lo-Coco F, Lowenberg B (2009) FLT3 inhibition as a targeted therapy for acute myeloid leukemia. Curr Opin Oncol 21:594–600PubMedCrossRef
20.
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R et al (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818PubMedCrossRef
21.
Lindhagen E, Eriksson A, Wickstrom M, Danielsson K, Grundmark B et al (2008) Significant cytotoxic activity in vitro of the EGFR tyrosine kinase inhibitor gefitinib in acute myeloblastic leukaemia. Eur J Haematol 81:344–353PubMed
22.
Boehrer S, Ades L, Galluzzi L, Tajeddine N, Tailler M et al (2008) Erlotinib and gefitinib for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a preclinical comparison. Biochem Pharmacol 76:1417–1425PubMedCrossRef
23.
Stegmaier K, Corsello SM, Ross KN, Wong JS, Deangelo DJ et al (2005) Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood 106:2841–2848PubMedCrossRef
24.
Hahn CK, Berchuck JE, Ross KN, Kakoza RM, Clauser K et al (2009) Proteomic and genetic approaches identify Syk as an AML target. Cancer Cell 16:281–294PubMedCrossRef
25.
Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E et al (2005) Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 105:54–60PubMedCrossRef
26.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456PubMedCrossRef
27.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281PubMedCrossRef
28.
Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M et al (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822–3829PubMedCrossRef
29.
EMEA EMA Document Number EMA/783677/2009. Accessed 2010/09/30 2010
30.
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 9:1451–1460PubMedCrossRef
31.
Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ et al (2005) Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106:3777–3784PubMedCrossRef
32.
Pessina A, Albella B, Bayo M, Bueren J, Brantom P et al (2003) Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics. Toxicol Sci 75:355–367PubMedCrossRef
Metadata
Title
In vitro evaluation of clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing normal tissues
Authors
Caroline Haglund
Anna Åleskog
Peter Nygren
Joachim Gullbo
Martin Höglund
Malin Wickström
Rolf Larsson
Elin Lindhagen
Publication date
01-03-2012
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-011-1746-1

Other articles of this Issue 3/2012

Cancer Chemotherapy and Pharmacology 3/2012 Go to the issue

Original Article

Feasibility of biweekly combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in patients with metastatic solid tumors: results of a two-step phase I trial: XELIRI and XELIRINOX

Original Article

Pharmacodynamics of DT-IgG, a dual-targeting antibody against VEGF-EGFR, in tumor xenografted mice

Original Article

miR-200bc/429 cluster modulates multidrug resistance of human cancer cell lines by targeting BCL2 and XIAP

Original Article

Phase II study of use of a single cycle of induction chemotherapy and concurrent chemoradiotherapy containing capecitabine/cisplatin followed by surgery for patients with resectable esophageal squamous cell carcinoma: long-term follow-up data

Original Article

Effect of food and a proton pump inhibitor on the pharmacokinetics of S-1 following oral administration of S-1 in patients with advanced solid tumors

Original Article

The role of MTHFR and RFC1 polymorphisms on toxicity and outcome of adult patients with hematological malignancies treated with high-dose methotrexate followed by leucovorin rescue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits