Interferon alfa-2a and 13-cis-retinoic acid in renal cell carcinoma: antitumor activity in a phase II trial and interactions in vitro.

Abstract

PURPOSE A phase II trial of interferon alfa-2a (IFN) and 13-cis-retinoic acid (CRA) was conducted in patients with renal cell carcinoma (RCC). In vitro studies were performed to investigate potential mechanisms of interaction. PATIENTS AND METHODS Forty-four patients were treated. IFN was given daily at 3 MU and escalated to 6 and 9 MU if tolerated. The dose of CRA was 1 mg/kg/d. The effects of combining CRA and IFN on the proliferation of five RCC cell lines were examined, and retinoid sensitivity was correlated to the expression of retinoic acid receptors. RESULTS Thirteen (30%) of 43 assessable patients achieved a major response (three complete and 10 partial). Responding sites included bone metastases and renal primary tumors. Seven responding patients remain progression-free at 10+ to 19+ months. The response proportion was higher than in our prior experience with IFN, which was 10% in 149 patients. Eleven of 12 renal cancer cell lines were resistant to CRA alone; one, SK-RC-06, showed 90% inhibition of cell growth. CRA augmented the antiproliferative effect of IFN in several IFN-sensitive cell lines, but not in IFN-resistant lines. Northern blot analysis showed that expression of retinoic acid receptor-beta (RAR-beta) was repressed and not induced by retinoic acid in retinoic acid-insensitive RCC lines. However, RAR-beta expression was induced by retinoic acid in SK-RC-06 cells. CONCLUSION IFN and CRA showed antitumor activity in patients with advanced RCC, and the proportion and nature of response suggested CRA added therapeutic benefit to IFN. A phase III randomized trial of IFN plus CRA versus IFN alone and a phase II trial of single-agent CRA have been initiated.

Capecitabine in the treatment of metastatic renal cell carcinoma

“…Retinoids are known to control many important biological processes, including differentation, morphogenesis, growth and tissue homeostasis (Warrel, 1994). Clinical and pre-clinical results provide evidence for an antiproliferative effect of 13-cis-retinoic acid in IFN-α-treated patients with renal cell carcinoma (Buer et al, 1995;Motzer et al, 1995). Furthermore, it seems to have a favourable effect in the treatment of renal Good prognosis was defined by the presence of lung metastases and the absence of bone metastases, ESR < 70 mm after 1 h, serum lactic dehydrogenase < 280 units l -1 , neutrophilic granulocytes < 6000 µl -1 and haemoglobin > 100 gm l -1 poor prognosis patients included all others Patients were entered between June 1998 and December 1998.…”

Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma

“…Curcumin is widely known for its chemopreventive and anticancer effects (47) and had proapoptotic effects in a RCC cell line, Caki-1 (48). Retinoic acid has been in clinical trials for cRCC in the past, in combination with IFN, with mixed results (49,50). The use of sFRP1 or Wnt inhibitors as therapeutics could benefit patients diagnosed with a variety of cancers, as loss of sFRP1 has been described in several different cancers, including many solid tumors (18,20,21) and hematopoietic malignancies (51).…”

Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, α-interferon (leucocyte) and tamoxifen

“…This assumption is also strengthened by the difference in costs between the two treatment arms (drug costs only: IL-2/IFN-a $27 000 vs $360 per patient in the tamoxifenonly group). However, the chemoimmunotherapy approach with and without 13-cis-retinoic acid (Motzer et al, 1995;Hanninen et al, 1996;Atzpodien et al, 1997) is exciting and suggests that unexpected regimens might exist that are better than any thus far tested. It is obvious that there is much need for investigation to find 'the optimal' application for immunotherapy in the clinical setting.…”