Rofstad E K
Institute for Cancer Research, Norwegian Radium Hospital, Oslo.
Br J Cancer. 1994 Sep;70(3):453-8. doi: 10.1038/bjc.1994.327.
Thermosensitisation by step-down heating (SDH) has previously been demonstrated in experimental rodent tumours. The purpose of the study reported here was to investigate whether the SDH effect in tumours in part may be attributed to heat-induced alterations in the capillary network and/or the microenvironment. Two human melanoma xenograft lines differing substantially in vascular parameters were selected for the study. A thermostatically regulated water bath was used for heat treatment. The conditioning treatment (44.5 degrees C or 45.5 degrees C for 15 min) was given in vivo, whereas the test treatment (42.0 degrees C for 45, 90, 135 or 180 min) was given either in vitro or in vivo. Treatment response was measured in vitro using a cell clonogenicity assay. Fraction of occluded vessels following heat treatment was assessed by examination of histological sections from tumours whose vascular network was filled with a contrast agent. Tumour bioenergetic status and tumour pH were measured by 31P magnetic resonance spectroscopy. The conditioning heat treatments caused significant vessel occlusion, decreased tumour bioenergetic status and decreased tumour pH in both tumour lines. The SDH effect measured when the test treatment was given in vivo was significantly increased relative to that measured when the test treatment was given in vitro. The magnitude of the increase showed a close relationship to fraction of occluded vessels, tumour bioenergetic status and tumour pH measured 90 min after treatment with 44.5 degrees C or 45.5 degrees C for 15 min. The increased SDH effect in vivo was probably attributable to tumour cells that were heat sensitive owing to the induction of low nutritional status and pH during the conditioning treatment. Consequently, the SDH effect in some tumours may in part be due to heat-induced alterations in the microenvironment. This suggests that SDH may be exploited clinically to achieve increased cell inactivation in tumours relative to the surrounding normal tissues.
先前已在实验性啮齿动物肿瘤中证实了通过逐步降温加热（SDH）实现的热致敏作用。本文所报告研究的目的是调查肿瘤中的SDH效应部分是否可归因于热诱导的毛细血管网络和/或微环境的改变。选择了两种在血管参数上有显著差异的人黑色素瘤异种移植系用于该研究。使用恒温调节水浴进行热处理。预处理（44.5℃或45.5℃持续15分钟）在体内进行，而测试处理（42.0℃持续45、90、135或180分钟）在体外或体内进行。使用细胞克隆形成试验在体外测量治疗反应。通过检查血管网络充满造影剂的肿瘤的组织切片来评估热处理后闭塞血管的比例。通过31P磁共振波谱测量肿瘤生物能量状态和肿瘤pH值。预处理热处理在两种肿瘤系中均导致显著的血管闭塞、肿瘤生物能量状态降低和肿瘤pH值降低。与在体外进行测试处理时所测量的SDH效应相比，在体内进行测试处理时所测量的SDH效应显著增加。增加的幅度与在44.5℃或45.5℃处理15分钟后90分钟所测量的闭塞血管比例、肿瘤生物能量状态和肿瘤pH值密切相关。体内SDH效应增加可能归因于在预处理过程中由于低营养状态和pH值的诱导而对热敏感的肿瘤细胞。因此，某些肿瘤中的SDH效应部分可能是由于热诱导的微环境改变。这表明SDH在临床上可能被用于相对于周围正常组织实现肿瘤中细胞失活的增加。
