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Heterogeneous activity of cytotoxic drugs in patient samples of peritoneal carcinomatosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Cancer Pharmacology and Informatics/Rolf Larsson)
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2008 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 34, no 5, 547-552 p.Article in journal (Refereed) Published
Abstract [en]

AIMS:

To investigate if the pattern of cytotoxic drug sensitivity in vitro in patient samples of peritoneal carcinomatosis (PC) is supportive to the current standardized approach for drug selection for perioperative intraperitoneal chemotherapy (IPC).

METHODS:

The cytotoxic effect of cisplatin, oxaliplatin, irinotecan, 5-fluorouracil, mitomycin-C, doxorubicin and melphalan was investigated in vitro on tumour cells from 223 patient tumour samples of different PC origins.

RESULTS:

Considerable differences in cytotoxic drug sensitivity between tumour types of the PC entity and within each tumour type were observed. Cisplatin showed high cross-resistance with oxaliplatin but low cross-resistance with doxorubicin and irinotecan. No cross-resistance was found between irinotecan and doxorubicin. The dose-response relationships for melphalan and irinotecan in individual samples showed great variability.

CONCLUSIONS:

The activity in vitro of cytotoxic drugs commonly used in IPC for PC is very heterogeneous. Efforts for individualizing drug selection for PC patients undergoing IPC seem justified.

Place, publisher, year, edition, pages
2008. Vol. 34, no 5, 547-552 p.
Keyword [en]
Peritoneal carcinomatosis, Intraperitoneal chemotherapy, Cytotoxic drug, In vitro
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-13245DOI: 10.1016/j.ejso.2007.05.002ISI: 000256207400012PubMedID: 17574369OAI: oai:DiVA.org:uu-13245DiVA: diva2:41015
Available from: 2008-06-24 Created: 2008-06-24 Last updated: 2017-12-11Bibliographically approved
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 675
Keyword
cytotoxic drug, in vitro assay, drug development, phase I clinical trial
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
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)
Opponent
Supervisors
Available from: 2011-05-13 Created: 2011-04-18 Last updated: 2011-07-01Bibliographically approved

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Mahteme, Hailevon Heideman, AnneGrundmark, BirgittaPåhlman, LarsGlimelius, BengtLarsson, RolfGraf, WilhelmNygren, Peter

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Mahteme, Hailevon Heideman, AnneGrundmark, BirgittaPåhlman, LarsGlimelius, BengtLarsson, RolfGraf, WilhelmNygren, Peter
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European Journal of Surgical Oncology
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