TREATMENT WITH TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-ALPHA OF A HUMAN KIDNEY CANCER XENOGRAFT IN NUDE-MICE - EVIDENCE FOR AN ANTICACHECTIC EFFECT OF INTERFERON-ALPHA

Unfortunately the efficacy of the treatment of the metastatic or recur rent renal cell carcinoma (RCC) has not improved during the last few y ears. Recently effort has been put into the experimental and clinical evaluation of so-called ''biological response modifiers'' (BRM; cytoki nes and related peptides) as treatment modalities for RCC. The present results are, however, still disappointing. Since BRM, if applied alon e, are largerly ineffective as antineoplastic agents, more experimenta l studies are now necessary to test the antineoplastic value of their combinations, which seem to be more promising. In the present study, t he in vivo effect of tumor necrosis factor alpha (TNF alpha) and/or in terferon on alpha (IFN alpha) on the macroscopic tumor growth (externa l caliper measurements of tumor size) and on the cell proliferation (i n vivo H-3-thymidine labelling index, LI, and mitotic index, MI) of a human RCC xenograft line in nude mice has been investigated. Neither o f these substances alone nor their combination was effective in changi ng the time course of the tumor sizes and the growth patterns of the t reated tumors in a statistically significant manner as compared to the untreated contrors. Also the cell kinetic parameters were only margin ally affected by these treatments, whereby TNF alpha alone proved to b e more effective than IFN alpha alone. However, compared to the effect of TNF alpha alone, the combination with IFN alpha leads to some amel ioration of the cell kinetic perturbations and also to an appreciable shift in the growth patterns of the tumors from distinct Gompertzian ( under TNF alpha alone) to near exponential (under the combination trea tment; p<0.05). As a consequence, the tumors grow more slowly under th e combined treatment during the observation time, and on the other han d, their growth does not decelerate as much as under TNF alpha alone. Actually, if tumor growth continues in the same way, the extrapolation of the present dat predicts smaller and greater tumors than the contr ol tumors in the TNF alpha and in the combination treatment groups res pectively. Notably, in the combination the effect of the IFN alpha see ms to predominate. This is also seen in the effect of this combination on the cachexia of these tumor-bearing animals: either alone or in co mbination with TNF alpha, IFN alpha partially protects the animals fro m tumor-growth associated weight loss. Although the direct antineoplas tic in vivo effect of the present cytokine combination against this hu man RCC xenografl line is rather limited, the potential antagonizing e ffect of IFN alpha on the development of cachexia should be further ex plored.