All-trans retinoic acid and interferon-alpha for treatment of human renal cell carcinoma multicellular tumor spheroids.

Introduction: Conventional preclinical investigations have strongly recommended to combine interferon-alpha (IFN-alpha) with 13-cis retinoic acid (13-cRA, isotretinoin) for treatment of renal cell carcinoma (RCC). However, a recent randomized controlled trial on the drug combination ultimately failed to demonstrate an increased tumor-specific survival of patients with metastatic RCC (MRCC). All-trans retinoic acid (ATRA, tretinoin) was suggested to provide stronger antineoplastic properties than 13-cRA in different other tumors.

Materials And Methods: The present study aimed to compare ATRA with 13-cRA (0.1, 1, 10, 100 nM) alone or in combination with IFN-alpha (5, 400, 5,000, 25,000, 250,000 IU/ml) or 5-fluorouracil (5-FU; 0.1, 1, 10, 100 microg/ml). Multicellular tumor spheroids of human RCC cells (SN12C) were treated in order to facilitate the predictions of the model system.

Results: ATRA decreased the mean volume of SN12C spheroids 10-20% more than 13-cRA. Both retinoids led to a super-additive growth inhibition in combination with IFN-alpha, but not with 5-FU. However, in this scenario the superior effect of ATRA compared to 13-cRA, although statistically significant, was not impressive (<10%).

Conclusions: ATRA provides a slightly stronger direct antineoplastic effect on human renal cancer cells than 13-cRA, and acts synergistically with IFN-alpha. However, ATRA, if at all, does not seem to be more suitable for treatment of patients with MRCC than 13-cRA.