Anticancer neuroimmunomodulation by pineal hormones other than melatonin: preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin.

Despite several years of experimental observations, the clinical application of the neuroimmunomodulation is still at the beginning. The pineal gland plays a main role in mediating the link between psychoneuroendocrine and immune systems. Melatonin (MLT), which is the main pineal hormone produced during the night, has appeared to amplify IL-2 anticancer activity. Other pineal hormones, however, would have immunomodulatory activity, in particular 5-methoxytryptophol (5-MTT), which is mainly produced during the light phase of the day. Previous clinical studies have shown that low-dose IL-2 plus MLT may have therapeutic efficacy in advanced cancer patients with neoplasms generally resistant to IL-2 alone, with a tumor regression rate generally less than 20% and an acceptable toxicity. The present study was carried out to evaluate the efficacy of low-dose IL-2 in association with both MLT and 5-MTT. The study included 14 untreatable advanced solid tumor patients (lung cancer: 4; gastric cancer: 3; mesothelioma: 2; hepatocarcinoma: 2; pancreatic cancer: 1; melanoma: 1; colon cancer: 1). IL-2 was injected subcutaneously at 3 MIU/day for 6 days/week for 4 weeks, by repeating a second cycle after a 21- day rest period. Both MLT and 5-MTT were given orally at 40 mg/day in the evening and at 1 mg/day at noon. The clinical results, as evaluated by WHO criteria after each cycle, consisted of partial response (PR) in 4/14 (29%) (lung cancer: 2; hepatocarcinoma: 1; mesothelioma: 1), stable disease (SD) in 6 and progressive disease in the last 4 patients. The treatment was extremely well tolerated in all patients, and in particular no fever greater than 38 degrees C occurred. These preliminary results show that the neuroimmunotherapy with low-dose IL-2 plus two pineal hormones, MLT and 5-MTT, is a well tolerated and potentially effective cancer therapy of untreatable advanced solid tumor patients, with results apparently superior with respect to those previously described with IL-2 plus MLT alone.