Carbogen and nicotinamide as radiosensitizers in a murine mammary carcinoma using conventional and accelerated radiotherapy

Rojas, Á.; Hirst, V.Kate; Calvert, Angela S.; Johns, H.

doi:10.1016/0360-3016(95)02087-x

Cited by 54 publications

(24 citation statements)

References 27 publications

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“…In certain cases carbogen has been shown to increase tumour pO 2 , while other studies failed to demonstrate increased TBF and oxygenation with carbogen (Song et al, 1987;Mason et al, 1991;Falk et al, 1992;Martin et al, 1993;Teicher et al, 1994;Brizel et al, 1995;Horsman et al, 1995;Powell et al, 1996Powell et al, , 1997Hill et al, 1998). In some animal models, irradiation combined with carbogen breathing has demonstrated increased survival and growth delay relative to irradiation alone, while others have failed to demonstrate any benefit (Inch et al, 1970; Martin et al, 1994;Rojas et al, 1996). Despite the above evidence that carbogen might be effective in reducing tumour hypoxia, a phase III randomized human trial comparing irradiation with carbogen to irradiation without carbogen failed to demonstrate a significant survival benefit or increase in loco-regional disease control (Rubin, 1979).…”

Section: Implications Of Co 2 Breathing On Efficacy Of Radiation Therapymentioning

confidence: 99%

The effects of hyperoxic and hypercarbic gases on tumour blood flow

et al. 1999

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Summary Carbogen (95% O 2 and 5% CO 2 ) has been used in preference to 100% oxygen (O 2 ) as a radiosensitizer, because it is believed that CO 2 blocks O 2 -induced vasoconstriction. However, recent work suggests that both normal and tumour arterioles of dorsal flap window chambers exhibit the opposite: no vasoconstriction vs constriction for O 2 vs carbogen breathing respectively. We hypothesized that CO 2 content might cause vasoconstriction and investigated the effects of three O 2 -CO 2 breathing mixtures on tumour arteriolar diameter (TAD) and blood flow (TBF). Fischer 344 rats with R3230Ac tumours transplanted into window chambers breathed either 1%, 5%, or 10% CO 2 + O 2 . Intravital microscopy and laser Doppler flowmetry were used to measure TAD and TBF respectively. Animals breathing 1% CO 2 had increased mean arterial pressure (MAP), no change in heart rate (HR), transient reduction in TAD and no change in TBF. Rats breathing 5% CO 2 (carbogen) had transiently increased MAP, decreased HR, reduced TAD and a sustained 25% TBF decrease. Animals exposed to 10% CO 2 experienced a transient decrease in MAP, no HR change, reduced TAD and a 30-40% transient TBF decrease. The effects on MAP, HR, TAD and TBF were not CO 2 dose-dependent, suggesting that complex physiologic mechanisms are involved. Nevertheless, when ≥ 5% CO 2 was breathed, there was clear vasoconstriction and TBF reduction in this model. This suggests that the effects of hypercarbic gases on TBF are site-dependent and that use of carbogen as a radiosensitizer may be counterproductive in certain situations.

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Section: Implications Of Co 2 Breathing On Efficacy Of Radiation Therapymentioning

confidence: 99%

The effects of hyperoxic and hypercarbic gases on tumour blood flow

et al. 1999

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“…In rodent tumours, nicotinamide plasma levels between 700-1000 nmol/ml achieve significant increases in radio sensitization over that of carbogen alone [14]. In this cur rent study we have demonstrated that these levels can be achieved in man with oral doses of 80 mg/kg but it is not always possible to reproduce such levels daily during a fractionated radiation treatment.…”

Section: 4 Dose Reduction Imentioning

confidence: 71%

“…in air without the drug, enhancement ratios in the order of 1.3-1.9 have been obtained for the combination of carbo gen and nicotinamide [3,12,14,15], Experimentally, plasma levels of 700 nmol/ml of nicotinamide are required at the time of irradiation to obtain a sensitising effect [8,15], Initial studies in healthy human volunteers showed that peak plasma levels of 800-1600 nmol/ml could be obtained after oral intake of 6 g [8,19]. Horsman et al showed that for maximal radiosensitization tumours should be inradiated at the time of peak drug levels [8].…”

Section: Introductionmentioning

confidence: 99%

Administration of nicotinamide during a five- to seven-week course of radiotherapy: pharmacokinetics, tolerance, and compliance

Kaanders

Stratford

Liefers

et al. 1997

Radiotherapy and Oncology

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Background and purpose: Nicotinamide was administered daily as a liquid formulation to head and neck cancer patients receiving a 5-to 7-week course of radiotherapy. The pharmacokinetics, compliance, and tolerance of this drug formulation were studied.Materials and methods: Blood samples were drawn and nicotinamide levels determined in 40 head and neck cancer patients. On the first treatment day serial samples were obtained followed by daily samples at the time of irradiation during the first and last full weeks of the treatment. Side-effects of nicotinamide were monitored.Results: In all patients peak concentrations greater than 700 nmol/ml could be obtained 0.25-3 h (mean 0.83 ± 0.73 h) after drug intake. During the first week of treatment plasma levels at the time of irradiation were adequate in 82% of the samples. This decreased to 59% in the last week of treatment which can be partly attributed to reduced compliance. The most important side-effect of nicotinamide was nausea with or without vomiting occurring in 65% of the patients. Severe side-effects were associated with high plasma concen trations over subsequent days. Tolerance improved after a 25% reduction of dose in six of seven patients but plasma levels at the time of irradiation fell below 700 nmol/ml in four out of six of these patients.Conclusions: Peak plasma concentrations above the 700 nmol/ml level were obtained in all patients but these concentrations could not be reproduced during the entire course of the treatment in a significant portion of the subjects. Side-effects of nicotinamide are associated with plasma concentrations and tolerance can be improved by a moderate reduction of dose.

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“…The combination of Accelerated Radiotherapy with CarbOgen breathing and Nicotinamide (ARCON) that was first proposed by Rojas et al is applied in the present study (35,36). Carbogen (95% O 2 and 5% CO 2 ) breathing causes a rise of the oxygen partial pressure in blood and tissues and reduces chronic hypoxia.…”

Section: Tumour Oxygenationmentioning

confidence: 99%

Clinical Outcome and Tumour Microenvironmental Effects of Accelerated Radiotherapy with Carbogen and Nicotinamide

Bussink¹

1999

Acta Oncologica

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Carbogen and nicotinamide as radiosensitizers in a murine mammary carcinoma using conventional and accelerated radiotherapy

Cited by 54 publications

References 27 publications

The effects of hyperoxic and hypercarbic gases on tumour blood flow

The effects of hyperoxic and hypercarbic gases on tumour blood flow

Administration of nicotinamide during a five- to seven-week course of radiotherapy: pharmacokinetics, tolerance, and compliance

Clinical Outcome and Tumour Microenvironmental Effects of Accelerated Radiotherapy with Carbogen and Nicotinamide

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