Mechanism of action of the selective tumor radiosensitizer nicotinamide

Horsman, Michael R.; Brown, J. Martin; Phil, D.; Hirst, V.Kate; Lemmon, Marilyn J.; Wood, Paul M.; Dunphy, Eamonn P.; Overgaard, Jens

doi:10.1016/0360-3016(88)90312-4

Cited by 66 publications

(14 citation statements)

References 26 publications

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“…The concomitant administration of these agents to tumour-bearing animals has consistently shown significant reductions in tumour HF (Horsman et al, 1988, Chaplin et al, 1991. The HFs of EMT-6 and R3327-AT tumours estimated from T/B ratios of IAZG were consistently and significantly reduced by the administration of nicotinamide and carbogen.…”

Section: Resultsmentioning

confidence: 96%

“…Tumour oxygenation was modulated by administration of 0.8 mg g-' nicotinamide plus carbogen, which had been shown to significantly reduce the hypoxic fractions in some rodent tumours (Horsman et al, 1988(Horsman et al, , 1990Chaplin et al, 1991). Nicotinamide was purchased from Sigma, prepared in sterile PBS at 160 mg ml' and administered i.p.…”

Section: Tumour Oxygen Modulationmentioning

confidence: 99%

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A dual hypoxic marker technique for measuring oxygenation change within individual tumors

Iyer

Kim²,

Schneider³

et al. 1998

Br J Cancer

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Summary Rodent tumour models have been the 'workhorse' for tumour oxygenation research and for investigating radiobiological hypoxic fraction. Because of the intertumour heterogeneity of blood flow and related parameters, most studies have pooled information derived from several different tumours to establish the statistical significance of specific measurements. But it is the oxygenation status of and its modulation in individual tumours that has important prognostic significance. In that regard, the bioreducible hypoxic marker technique was tested for its potential to quantify oxygenation changes within individual tumours. f-D-lodinated azomycin galactoside (IAZG) and P-Diodinated azomycin xylopyranoside (IAZXP) were each radiolabelled with lodine-125 and iodine-131 for measurements of animal tumour oxygenation. The tumour-blood (T/B) ratio of marker radioactivity in mice after the renal excretion of unbound marker (at 3 h and longer times) had been shown to be proportional to radiobiological hypoxic fraction. When markers labelled with both radioisotopes were administered simultaneously to EMT-6 tumour-bearing scid mice, T/B ratios were found to vary by up to 300% between different tumours, with an average intratumour variation of only -4%. When the markers were administered 2.5-3.0 h apart, changes in T/B ratios of 8-25% were observed in 10 out of 28 (36%) tumours. Changes to both higher and lower hypoxic fraction were observed, suggestive of acute or cycling hypoxia. When 0.8 mg g-1 nicotinamide plus carbogen was administered to increase tumour oxygenation, reductions in T/B ratios (mean AT/B -38%) were observed in all tumours. Similar results were obtained with Dunning rat prostate carcinomas growing in Fischer X Copenhagen rats whose T/B ratios of IAZG and radiobiological hypoxic fractions are significantly lower. These studies suggest that fluctuating hypoxia can account for at least 25% of the total hypoxic fraction in some tumours and that correlations between bioreducible marker avidity and related tumour properties will be optimal when the independent assays are performed over the same time period. This dual hypoxic marker technique should prove useful for investigating both spontaneous and induced oxygenation changes within individual rodent tumours.

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Section: Resultsmentioning

confidence: 96%

Section: Tumour Oxygen Modulationmentioning

confidence: 99%

A dual hypoxic marker technique for measuring oxygenation change within individual tumors

Iyer

Kim²,

Schneider³

et al. 1998

Br J Cancer

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“…Breathing carbogen increases the amount of dissolved oxygen in the plasma at the capillary level and this, assisted by hypercapnic-induced vasodilation, may allow diffusion of oxygen into chronically hypoxic regions of tumours, resulting in an increase in tumour oxygenation. Nicotinamide is thought to reduce the occurrence of acute hypoxia (Chaplin et al, 1990) and hence increase tumour blood flow (Horsman et al, 1988;Hirst et al, 1993), although its precise mechanism of action is still unclear. The combination of carbogen breathing and nicotinamide is currently being re-evaluated in the clinic as a strategy to overcome hypoxic cell radioresistance Kaanders et al, 1998;Bernier et al, 1999).…”

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confidence: 99%

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et al. 2000

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Summary Both host carbogen (95% oxygen/5% carbon dioxide) breathing and nicotinamide administration enhance tumour radiotherapeutic response and are being re-evaluated in the clinic. Non-invasive magnetic resonance imaging (MRI) and 31 P magnetic resonance spectroscopy (MRS) methods have been used to give information on the effects of nicotinamide alone and in combination with host carbogen breathing on transplanted rat GH3 prolactinomas. Gradient recalled echo (GRE) MRI, sensitive to blood oxygenation changes, and spin echo (SE) MRI, sensitive to perfusion/flow, showed large signal intensity increases with carbogen breathing. Nicotinamide, thought to act by suppressing the transient closure of small blood vessels that cause intermittent tumour hypoxia, induced a small increase in blood oxygenation but no detectable change in perfusion/flow. Carbogen combined with nicotinamide was no more effective than carbogen alone. Both carbogen and nicotinamide caused significant increases in the nucleoside triphosphate/inorganic phosphate (βNTP/P i ) ratio, implying that the tumour cells normally receive sub-optimal substrate supply, and is consistent with either increased glycolysis and/or a switch to more oxidative metabolism. The most striking observation was the marked increase in blood glucose (twofold) induced by both nicotinamide and carbogen. Whether this may play a role in tumour radiosensitivity has yet to be determined.

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“…It has been suggested, based largely on studies with cells in culture that each of these compounds can inhibit the effective repair of DNA damage in irradiated mammalian cells (Ben Hur, 1983;Pero et al, 1989). There is also ample evidence to show that NA at high doses significantly increases blood flow to intradermal mouse tumours (Horsman et al, 1988;Horsman et al, 1989a). MCA has been shown to potentiate the cell killing effects of radiation and cisplatin in a subcutaneous human carcinoma xenograft in the mouse Lybak et al, 1990; …”

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confidence: 99%

“…The latter will be more important when considering the exposure of tissues to anticancer agents in the circulating blood. The Rb extraction method gives this information; it also gives a volume (Jonsson et al, 1985;Horsman et al, 1986) and there is considerable evidence that regional blood flow modification is responsible for at least part of this effect through oxygenation of radioresistant hypoxic cells (Chaplin et al, 1990;Horsman et al, 1988;Horsman et al, 1989a). Rb extraction was one end point used in one of these studies (Horsman et al, 1988) using the RIF-1 tumour growing in the skin.…”

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confidence: 99%

Blood flow modification by nicotinamide and metoclopramide in mouse tumours growing in different sites

Hirst

Joiner²,

Hirst³

1993

Br J Cancer

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Summary Nicotinamide (NA) and metoclopramide (MCA) have been shown to be sensitisers of the effects of radiation and drugs in experimental rodent tumours growing in skin and muscle. We have used 86Rb uptake to investigate the effects of these two drugs on the distribution of blood to a mouse carcinoma (NT) growing in skin, muscle or the gut wall, as well as to the host normal tissue. NA caused an increase in cardiac output distribution (COD) of between 17 and 92% to tumours in the three sites. When this increase is related to the changes in COD to the host normal tissues, however, COD to tumours in skin and muscle was increased by a factor of 1.8 and to tumours in the gut wall by a factor of 1.7. MCA caused a consistent increase in COD to tumours growing in muscle, but the effects in tumours in skin and gut were variable with time. Again when related to the change in COD to host normal tissues, a factor of 2.1 was seen for COD to tumours growing in muscle and gut. Both NA and MCA alter COD to tumours in some sites relative to host tissues in a way that could enhance anti-cancer drug delivery to tumours, though the effects of NA are more reliable in our systems.

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Mechanism of action of the selective tumor radiosensitizer nicotinamide

Cited by 66 publications

References 26 publications

A dual hypoxic marker technique for measuring oxygenation change within individual tumors

A dual hypoxic marker technique for measuring oxygenation change within individual tumors

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Blood flow modification by nicotinamide and metoclopramide in mouse tumours growing in different sites

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