el Gamoussi R, Threadgill M D, Prade M, Stratford I J, Guichard M
Laboratoire de Radiobiologie Cellulaire (Unité Inserm 247), Institut Gustave-Roussy, Villejuif, France.
Cancer Chemother Pharmacol. 1993;31(4):277-82. doi: 10.1007/BF00685671.
The intra-cellular uptake of the weakly basic radiosensitiser pimonidazole (PIMO) was determined as a function of the pigmentation of Na11+ human melanotic melanoma cells in vitro. Two experimental conditions were considered: exponentially growing cells (Exp.) and plateau-phase cells (PI.). The melanin content of Na11+ cells ranged from 500 micrograms/g cell weight in exponentially growing cells to 6000 micrograms/g in heavily pigmented plateau-phase cells. Cells were exposed to PIMO (medium dose, 0.2 mmol/dm3; 58.2 micrograms/ml). The intra-cellular concentration ranged from 163 micrograms/g in Exp. to 900 micrograms/g in pigmented Pl.; the latter being equivalent to an intra- to extracellular concentration ratio (Ci/Ce) of 17. However, this increase in the cellular uptake of PIMO was not accompanied by an increase in radiosensitising efficiency. In comparison, the Ci/Ce for etanidazole (ETA), a radiosensitiser that is uncharged at physiological pH, remained approximately constant at 1 for all values of melanin contents. Treatment of Na11+ tumours in vivo with [3H]-PIMO resulted in a tumour:blood ratio of about 3 at 30-60 min after administration. However, at 24 h a grain count of label derived from [3H]-PIMO showed that picnotic areas of tumours contained levels that were some 40 times greater than the background value. This high level of label was coincident with areas of highest apparent melanin content. In conclusion, PIMO accumulates in very heavily pigmented melanoma cells present in necrotic zones with picnosis. As these cells are probably non-clonogenic, PIMO is not suitable for use in melanoma radiotherapy.
在体外，测定了弱碱性放射增敏剂匹莫硝唑（PIMO）在Na11 +人黑色素瘤细胞中的细胞内摄取情况，该摄取情况是细胞色素沉着的函数。考虑了两种实验条件：指数生长期细胞（Exp.）和平台期细胞（PI.）。Na11 +细胞的黑色素含量范围从指数生长期细胞的500微克/克细胞重量到色素沉着严重的平台期细胞的6000微克/克。将细胞暴露于PIMO（中等剂量，0.2 mmol/dm3；58.2微克/毫升）。细胞内浓度范围从指数生长期细胞的163微克/克到色素沉着的平台期细胞的900微克/克；后者相当于细胞内与细胞外浓度比（Ci/Ce）为17。然而，PIMO细胞摄取的这种增加并未伴随着放射增敏效率的增加。相比之下，对于在生理pH下不带电荷的放射增敏剂依他硝唑（ETA），Ci/Ce在所有黑色素含量值下均保持在约1不变。用[3H]-PIMO对体内的Na11 +肿瘤进行治疗，给药后30 - 60分钟肿瘤与血液的比率约为3。然而，在24小时时，源自[3H]-PIMO的标记颗粒计数表明，肿瘤的固缩区域所含水平比背景值高约40倍。这种高标记水平与黑色素含量最高的区域一致。总之，PIMO在坏死区存在的色素沉着非常严重的黑色素瘤细胞中积累并发生固缩。由于这些细胞可能是非克隆性的，PIMO不适合用于黑色素瘤放疗。
