Lissoni P, Barni S, Tancini G, Ardizzoia A, Ricci G, Aldeghi R, Brivio F, Tisi E, Rovelli F, Rescaldani R
Divisione di Radioterapia, San Gerardo Hospital, Milan, Italy.
Br J Cancer. 1994 Jan;69(1):196-9. doi: 10.1038/bjc.1994.34.
Our previous experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In particular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumour regressions in neoplasms that are generally non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patients with solid tumours other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomised to be treated with IL-2 alone subcutaneously (3 million IU day-1 at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day-1 orally at 8.00 p.m. every day starting 7 days before IL-2). A complete response was obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients treated with IL-2 alone. Tumour objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39, P < 0.001). The survival at 1 year was significantly higher in patients treated with IL-2 and MLT than in the IL-2 group (19/41 vs 6/39, P < 0.05). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher in the IL-2 plus MLT group than in patients treated with IL-2 alone; on the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study shows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy.
我们先前的实验研究表明，提高白细胞介素2（IL-2）生物抗肿瘤活性的最佳方法不是与另一种细胞因子联合使用，而是与免疫调节神经激素联合使用，以重现心理内分泌系统和免疫系统之间的生理联系，这在免疫反应调节中起着重要作用。特别是，与松果体神经激素褪黑素（MLT）联合使用已被证明可使通常对单独使用IL-2无反应的肿瘤发生肿瘤消退。为了证实这些初步结果，对局部晚期或转移性实体瘤（肾细胞癌和黑色素瘤除外）患者进行了一项临床试验。该研究纳入了80例连续患者，他们被随机分为单独皮下注射IL-2治疗（每周6天，晚上8点皮下注射300万IU，共4周）或IL-2加MLT治疗（在开始IL-2治疗前7天起，每天晚上8点口服40mg）。接受IL-2加MLT治疗的41例患者中有3例获得完全缓解，而单独接受IL-2治疗的患者无一例完全缓解。接受IL-2加MLT治疗的41例患者中有8例获得部分缓解，而单独接受IL-2治疗的39例患者中只有1例获得部分缓解。接受IL-2和MLT治疗的患者的肿瘤客观缓解率显著高于单独接受IL-2治疗的患者（11/41对1/39，P<0.001）。接受IL-2和MLT治疗的患者1年生存率显著高于IL-2组（19/41对6/39，P<0.05）。最后，IL-2加MLT组患者淋巴细胞和嗜酸性粒细胞数量的平均增加显著高于单独接受IL-2治疗的患者；相反，单独接受IL-2治疗的患者巨噬细胞激活特异性标志物新蝶呤的平均增加显著更高。两组患者对治疗的耐受性都很好。这项研究表明，松果体激素MLT的联合使用可能会提高低剂量IL-2皮下治疗的疗效。
