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 appli cation of the neuroimmunomodulation is still at the beginning. The pin eal gland plays a main role in mediating the link between psyconeuroen docrine and immune systems. Melatonin (MLT), which is the main pineal hormone produced during the night, has appeared to amplify IL-2 antica ncer activity Other pineal hormones, however; would have immunomodulat ory activity, in particular-5-methoxytryptophol (5-MTT), which is main ly produced during the light phase of the day. Previous clinical studi es have shown that low-dose IL-2 plus MLT may have therapeutic efficac y 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 canc er:4;gastric cancer:3;mesothelioma:2; hepatocarcinoma:2, pancreatic ca ncer: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 I mg/day at noon. The clinical results, a s evaluated by WHO criteria after each cycle, consisted of partial res ponse (PR) in 4/14 (29%) (lung cancer:2;hepatocarcinoma: 1; mesothelio ma. 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 pote ntially effective cancer therapy of untreatable advanced solid tumor p atients, with results apparently superior with respect to those previo usly described with IL-2 plus MLT alone.