Nicotinamide and Carbogen: Relationship betweenpO₂and Radiosensitivity in Three Tumour Lines

Abstract

The effects of carbogen breathing, nicotinamide injection and their combination on tumour radiosensitivity were correlated with changes in tumour O2 tension to determine the relationship between radiosensitivity and measured pO2. The radiosensitivity (in vivo-in vitro colony assay) and O2 tension (computerized pO2 histograph KIMOC 6650) of two human xenografted tumours (HRT18 and Na11+) and one murine tumour (EMT6) were measured under similar experimental conditions. A single dose of radiation was delivered (8 Gy for HRT18 and Na11+, 12 Gy for EMT6). Carbogen breathing, nicotinamide injection, and their combination all significantly increased radiosensitivity in the three cell lines (p < 0.05); the most efficient treatment was carbogen plus nicotinamide. The radiosensitization was optimum for EMT6 and Na11+. Mean and median pO2 increased with all three treatments, except for carbogen breathing in EMT6. Carbogen breathing had little effect on the proportion of low pO2 values, but induced pO2 values > 30 mmHg in all three tumour lines. Nicotinamide decreased the proportion of low pO2 values. This effect is larger with the combination carbogen plus nicotinamide. Almost all pO2 values < 2.5 mmHg were eliminated for HRT18 and EMT6. The relationship between radiosensitization and pO2 was significant when pO2 was expressed as the percentage of values below 7, 8, 9 and 10 mmHg for the three lines.

Detection of hypoxic cells in a C3H mouse mammary carcinoma using the comet assay

“…However, there is an apparent inability to correlate pO2 measurements with hypoxic fraction across different tumour types Martin et al, 1994;Kavanagh et al, 1996). Gerwick et al (1995) (Franko et al, 1987;Cline et al, 1994).…”

The effects of carbogen and nicotinamide on intravascular oxyhaemoglobin saturations in SCCVII and KHT murine tumours

“…Since tumour radiosensitivity is commonly calculated from the ratio of the fraction of anoxic clonogenic tumour cells to the fraction of total clonogenic cells (Moulder and Rockwell, 1984), it follows that if substantially different proportions of clonogenic and non-clonogenic tumour cells are oxygenated by the alternative treatments, direct measures of tumour oxygenation will not correlate with changes in radiosensitivity (Fenton et al, 1995). Thus, although clear relationships may be demonstrated within specific tumour lines (Rofstad et al, 1988;Horsman et al, 1993), attempts to define smilar correlations across tumour lines have proven unsuccessful (Rofstad et al, 1988;Horsman et al, 1995;Martin et al, 1994).…”

“…As was the case for the HbO2 measurements, pO2 levels following NIC were not different from the air-breathing controls. In the studies of Martin et al (1994) (Moulder and Rockwell, 1984;Fenton et al, 1995). As described more fully in a previous theoretical study (Fenton et al, 1995), HF determinations can vary independently of directly measured changes in tumour oxygenation within the non-clonogenic subpopulation.…”

“…Finally, in the SCCVII carcinoma, carbogen and NIC were equivalent, while the combination was superior (Chaplin et al, 1993). Measurements of alterations in tumour oxygenation following these agents have also varied markedly with tumour line (Lee and Song, 1992;Fenton and Boyce, 1993; Kelleher and Vaupel, 1993;Horsman et al, 1995;Martin et al, 1994). A key question is whether a relationship exists between direct measures of tumour oxygenation and corresponding determinations of tumour radiosensitivity.…”

“…Several recent reports have indicated that either carbogen breathing (95% oxygen, 5% carbon dioxide) or nicotinamide (NIC) administration, alone or in combination, can effectively radiosensitise tumours in mice (Rojas, 1991;Chaplin et al, 1993;Simon et al, 1993;Siemann et al, 1994;Done et al, 1994;Martin et al, 1994). It is generally believed that carbogen breathing improves response by increasing the amount of oxygen physically dissolved in the blood, thereby increasing the distance the oxygen is able to diffuse from the blood vessels to the tumour cells, and possibly by increasing tumour blood flow (Kruuv et al, 1967).…”