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Is sensitization with nicotinamide and carbogen dependent on nicotinamide concentration at the time of irradiation?
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
2004 (English)In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 80, no 7, 499-506 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To determine whether tumour radiosensitization and the therapeutic benefit of administering carbogen with nicotinamide depend upon irradiating at the time of peak drug concentration. MATERIALS AND METHODS: Local tumour control of CaNT tumours in CBA mice and acute skin reactions in albino WHT mice were assessed after treatment with 10 X-ray fractions in air, carbogen alone or combined with 0.1, 0.2 or 0.5 mg g(-1) nicotinamide, injected 15, 30 or 60 min before irradiation. Plasma and tumour drug pharmacokinetics were performed. RESULTS: Nicotinamide was rapidly taken up into tumours; a six- and threefold higher concentration was obtained with 0.5 mg g(-1) compared with 0.1 and 0.2 mg g(-1), respectively. Tumour, but not skin, radiosensitization increased as the dose of nicotinamide increased (p = 0.03), but at each dose level there was no significant difference in radiosensitivity when irradiations were done at or after the time of peak concentration. An almost eightfold increase in plasma levels increased tumour enhancement ratios from 1.74 to 1.92 (p < 0.0001). In tumours all schedules gave significant enhancement relative to carbogen alone (p < or = 0.04). CONCLUSIONS: Tumour and skin radiosensitivity was independent of time of nicotinamide administration. Higher drug concentrations were not mirrored by proportionally higher enhancement ratios. Lower plasma levels than previously suggested significantly enhanced tumour radiosensitivity relative to carbogen alone. The clinical implications of these findings are discussed.

Place, publisher, year, edition, pages
2004. Vol. 80, no 7, 499-506 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-15542DOI: 10.1080/09553000410001724199PubMedID: 15360088OAI: diva2:155214
Available from: 2006-11-13 Created: 2006-11-13 Last updated: 2010-08-11Bibliographically approved
In thesis
1. ARCON in experimental and clinical radiotherapy
Open this publication in new window or tab >>ARCON in experimental and clinical radiotherapy
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

xHypoxia and repopulation of tumour clonogens are two important determinants of treatment outcome in radiotherapy. In general clinical evidence indicates that loco-regional control may be reduced with long overall treatment times and for tumours with low pre-treatment levels of oxygen. Experimental studies with normobaric carbogen and oxygen showed a two-fold enhancement of the efficacy of radiation in a mouse tumour model when combining oxygen with treatment acceleration. It was then demonstrated that substituting carbogen for oxygen and adding high-dose nicotinamide (NAM) further increased the effect. These findings became the basis for a multi-factorial approach designed to overcome the radioprotective effect of tumour repopulation and that of perfusion–limited and diffusion–limited hypoxia. The strategy, named ARCON, combines Accelerated Radiotherapy with CarbOgen and Nicotinamide.

Experimental evaluation of ARCON

The therapeutic potential of carbogen combined with NAM (CON) focusing on treatment schedules that use clinically relevant radiation and drug dose levels was evaluated in tumour and normal tissue animal models. Some of the conditions under which ARCON gives the largest degree of tumour radiosensitization and therapeutic benefit were identified. Specifically, NAM-dose level, pharmacokinetics and scheduling, and the effect of NAM on repair processes in vivo were also investigated. The results showed that in conventional and accelerated radiotherapy, carbogen and CON are effective and relatively non-toxic tumour sensitizers. They also demonstrated that tumour sensitization with CON was independent of time of NAM administration but that it was drug dose dependent. Some degree of normal tissue sensitization was observed but even relative to mouse skin a significant therapeutic gain was achieved. The mechanism of action for NAM sensitization originally proposed was that of repair inhibition. In the in vivo mouse models tested, namely skin and kidney, NAM did not alter the rate nor the magnitude of repair of radiation induced damage.

Clinical evaluation of ARCON

In the early 90s, various centres, particularly in the UK, Sweden, Holland and Switzerland, undertook clinical trials of ARCON. The protocols were designed based on detailed considerations of the rodent and human radiation and pharmacokinetic studies. This document also discusses the findings of a phase II non-randomized trial in advanced bladder cancer of accelerated radiotherapy combined with carbogen alone and ARCON. The aim of the study was to establish the feasibility of administering carbogen and NAM to patients and to determine the extent of early and late normal tissue damage. Historical comparisons suggested no overt increase in normal tissue radiosensitivity and the data indicate that ARCON could achieve a therapeutic gain in advanced bladder cancer.

49 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 872
Oncology, ARCON, tumours, normal tissues, radiosensitization, carbogen, nicotinamide, repair inhibition, therapeutic gain, rodents, humans, Onkologi
National Category
Cancer and Oncology
Research subject
urn:nbn:se:umu:diva-207 (URN)91-7305-582-4 (ISBN)
Public defence
2004-04-28, Sal 244, 7, Norrlands universitetssjukhus, Umeå, 09:00
Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2010-08-11Bibliographically approved

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