STEP-DOWN HEATING OF HUMAN-MELANOMA XENOGRAFTS - EFFECTS OF THE TUMORMICROENVIRONMENT

Thermosensitisation by step-down heating (SDH) has previously been dem onstrated in experimental rodent tumours. The purpose of the study rep orted here was to investigate whether the SDH effect in tumours in par t may be attributed to heat-induced alterations in the capillary netwo rk and/or the microenvironment. Two human melanoma xenograft lines dif fering substantially in vascular parameters were selected for the stud y. 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. Treatme nt response was measured in vitro using a cell clonogenicity assay. Fr action of occluded Vessels following heat treatment was assessed by ex amination of histological sections from tumours whose vascular network was filled with a contrast agent. Tumour bioenergetic status and tumo ur pH were measured by P-31 magnetic resonance spectroscopy. The condi tioning heat treatments caused significant vessel occlusion, decreased tumour bioenergetic status and decreased tumour pH in both tumour lin es. The SDH effect measured when the test treatment was given in vivo was significantly increased relative to that measured when the test tr eatment was given in vitro. The magnitude of the increase showed a clo se relationship to fraction of occluded vessels, tumour bioenergetic s tatus 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 p robably attributable to tumour cells that were heat sensitive owing to the induction of low nutritional status and pH during the conditionin g treatment. Consequently, the SDH effect in some tumours may in part be due to heat-induced alterations in the microenvironment. This sugge sts that SDH may be exploited clinically to achieve increased cell ina ctivation in tumours relative to the surrounding normal tissues.