Alterations of tumour cells, stroma and apoptosis in rat prostatic adenocarcinoma following treatment with histamine, interleukin-2 and irradiation.

The present study was designed to determine whether IL-2 and histamine alone, or in combination could modulate the effects of irradiation on Dunning (R3327) rat adenocarcinomas at the cellular level. Copenhagen x Fisher rats carrying bilateral tumours in the flank were used. When the tumours had a median volume of 150 mm3, one group of rats was treated with histamine alone (4 mgkg-1 subcutaneously on week days), another group with interleukin-2 (IL-2) alone (425 IU kg-1 continuous infusion) and a third group with both histamine and IL-2 during 6 weeks. Irradiation was given one week after the onset of treatment with histamine and/or IL-2, with a linear accelerator 6 MV, in a dose of 6 Gy/day for 3 days to the tumour of one side, while the other side served as control. Morphometric analyses of the amount of cystic structures, volume density for tumour epithelium, stroma and acinar lumina, the number of activated macrophages and natural killer cells (NK-cells) and in situ detection of apoptotic cells was carried out 5 weeks after the irradiation, when the experiment was ceased. The combination of IL-2 with histamine and irradiation significantly augmented the reduction of tumour cells (p < 0.002) and increased the number of apoptotic cells (p < 0.007) compared to irradiation alone. The number of cystic structures within tumour tissue increased in all tumours that received histamine, but was most pronounced in the three combination group. A strong negative correlation between the epithelial cells and the apoptotic index (rs = -0.61, p < 0.0001) and a strong positive correlation between the stroma and the apoptotic index (rs = 0.59, p < 0.001) was found. A prominent infiltration of activated macrophages was observed in the irradiated group. This infiltration was impaired by the drugs. The results suggested that the used three modality treatment could be of value in increasing the efficacy of local radiotherapy concomitantly with a most plausible effect on micrometastatic spread. The results also propose that volume measurements alone are not an optimal parameter when evaluating effects of new treatment modalities.