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Assessment of Chemotherapeutic Drug Sensitivity in Epithelial Ovarian Cancer Using Primary Cultures of Tumour Cells from Patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Sensitivity of epithelial ovarian cancer to chemotherapeutic drugs relevant in treatment of this cancer type was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to histopathological subtypes, treatment status and clinical tumour response. For cisplatin, doxorubicin, 5-FU, cyclophosphamide and topotecan, seropapillary high grade and clear cell ovarian cancer were the most sensitive subtypes and the mucinous tumours the most resistant subtype, whereas endometrioid tumours and the seropapillary low grade/borderline tumours showed intermediate sensitivity. In contrast, docetaxel showed the opposite pattern of activity. Samples from patients previously treated with chemotherapy tended, for the majority of drugs, to be slightly more resistant than samples from treatment naïve patients. The activity of cisplatin correlated strongly with that of the other drugs with the exception of docetaxel, implicating non-cross resistance between these key drugs in ovarian cancer. Tumour samples from two sites in the same patient at the same occasion showed similar and samples taken at different occasions different cisplatin sensitivity, which may implicate tumour clonal selection over time. At group level, samples from patients clinically responding to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, optimized analyses of drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 90 – 100% and 54 – 83% ranges, respectively. In conclusion, ovarian cancer subtypes exhibit different chemotherapeutic drug sensitivity in vitro, which needs consideration in treatment decisions for this disease. Furthermore, in vitro assessment of ovarian cancer tumour cell chemotherapeutic drug sensitivity provides clinically relevant information that could be useful in efforts to optimize treatment in individual patients with this disease.

Keyword [en]
ovarian cancer, chemotherapy, drug sensitivity testing, in vitro
National Category
Cancer and Oncology
URN: urn:nbn:se:uu:diva-151799OAI: oai:DiVA.org:uu-151799DiVA: diva2:411385
Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2013-08-15
In thesis
1. Exploring Cancer Drugs In Vitro and In Vivo: With Special Reference to Chemosensitivity Testing and Early Clinical Development
Open this publication in new window or tab >>Exploring Cancer Drugs In Vitro and In Vivo: With Special Reference to Chemosensitivity Testing and Early Clinical Development
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aims of this thesis were to investigate the utility of in vitro drug sensitivity testing to optimize the use of cancer chemotherapy and to assess the properties of a new cancer drug in a phase I clinical trial. Tumour cells from patients were analysed with the short-term Fluorometric Microculture Cytotoxicity Assay (FMCA). In samples from a wide spectrum of tumour types, the effect of the drug combination FEC (5Fu-epirubicin-cyclophosphamide) was generally appropriately predicted from the effect of the best component drug. However, of samples intermediately sensitive to the best single drug, 45% converted to sensitive when testing the combination. Thus, combination testing may identify advantageous interactions and improve in vitro test performance. In tumour samples from peritoneal carcinomatosis, significant differences in drug sensitivity between diagnoses were observed, cross-resistance between most drugs was modest or absent, and the concentration-effect relationships for two drugs in individual samples varied considerably. Thus, for optimal selection of drugs for intraperitoneal chemotherapy, differences in drug sensitivity at the diagnosis and individual patient level should be considered. In samples from patients with ovarian carcinoma, drug sensitivity was related to tumour grade, histologic subtype and patient treatment status. In a homogeneous subset of patients, the FMCA predicted individual patient tumour response with high sensitivity and specificity. Thus, if carefully interpreted in the context of important clinical variables, in vitro testing could be of value for individualizing chemotherapy in ovarian cancer. Employing a once weekly dosing schedule in a phase I trial, the mechanistically new and preclinically promising NAD depleting drug CHS 828 produced dose limiting thrombocytopenia and gastrointestinal toxicity without clear evidence of anti-tumour efficacy. It is concluded that in vitro drug sensitivity testing could be a way to optimize the use of chemotherapy and that successful development of new cancer drugs needs improved strategies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 52 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 675
cytotoxic drug, in vitro assay, drug development, phase I clinical trial
National Category
Cancer and Oncology
Research subject
urn:nbn:se:uu:diva-151826 (URN)978-91-554-8087-5 (ISBN)
Public defence
2011-06-03, Auditorium Minus, Gustavianum, Uppsala, 09:15 (English)
Available from: 2011-05-13 Created: 2011-04-18 Last updated: 2011-07-01Bibliographically approved

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von Heideman, AnneGrundmark, BirgittaMahteme, Haile
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OncologyDepartment of Surgical SciencesDepartment of Women's and Children's HealthClinical Pharmacology
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