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Radiosensitisation in normal tissues with oxygen, carbogen and nicotinamide: therapeutic gain comparisons for fractionated X-ray schedules
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1996 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 39, no 1, 53-64 p.Article in journal (Refereed) Published
Abstract [en]

METHODS: Radiosensitisation with oxygen, carbogen or nicotinamide alone and oxygen or carbogen combined with nicotinamide was compared in early and late responding normal tissues in rodents. X-ray treatments were delivered as single doses or fractionated schedules of 2 fractions in 1 day, 2, 12 and 36 fractions in an overall time of 12 days and 10 fractions in 5 or 12 days. Acute skin reactions, survival of intestinal crypts, breathing rate, reduction in the packed red-cell volume and clearance of 51Cr-EDTA were used as assays of epidermal, gut, lung and renal damage. RESULTS: Relative to air-breathing mice, carbogen or oxygen produced a small, and not always significant, increase in sensitivity (enhancement ratios < or = 1.15) in gut, lung and kidneys; however, in skin a dose enhancement of 1.2-1.3 was observed. The effect of nicotinamide in air, carbogen or oxygen was studied only in lung and gut. The drug produced variable but generally significant increases in radiosensitisation ( < or = 1.26) in all three gases. Relative to treatments in air, enhancement ratios for nicotinamide alone were usually slightly higher than those observed when either carbogen or oxygen were administered without the drug. With all three modifiers (i.e. oxygen, carbogen, nicotinamide alone or for the drug-gas combinations) there was no significant change in the enhancement ratios observed as the number of radiation dose fractions was varied. CONCLUSIONS: Comparisons with fractionated X-ray studies done previously in rodent tumours indicate that a therapeutic benefit, relative to lung, gut and renal damage, would be observed with oxygen or carbogen alone but not with nicotinamide alone. The greatest gain would be achieved with the combination of carbogen and nicotinamide, with which a benefit was observed even relative to epidermal damage. These results indicate that some decrease in normal tissue tolerance could be observed when using these modifiers in clinical radiotherapy and, although small, the appropriate dose reductions should be considered; caution should be exercised especially when carbogen and nicotinamide are used in conjunction with the more radical accelerated schedules.

Place, publisher, year, edition, pages
1996. Vol. 39, no 1, 53-64 p.
Keyword [en]
Oxygen, Carbogen, Nicotinamide, ARCON, Skin, Lung, Gut, Kidney, Fractionation, Therapeutic benefit
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-3776DOI: 10.1016/0167-8140(95)01678-3PubMedID: 8735494OAI: diva2:142644
Available from: 2004-03-11 Created: 2004-03-11 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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