给免疫治疗“减毒增效”的辅助药物（十三）：松果体吲哚

松果体吲哚主要包括褪黑素、5-methoxytriptamine (5-MTT)、5-methoxytryptophol (5-MTP) 、 5-methoxy-indole acetic acid (5-MIA)四种。

- |: k3 D1 e+ O2 ~5 p1 f5 f1 j褪黑素抑制treg、促进淋巴细胞分泌IL-2又消炎，实乃免疫治疗的良配。褪黑素增强免疫抗癌的临床试验我们之前讲了不少。

* A5 k6 q: Y" r其他三种松果体吲哚增强免疫抗癌的作用也都经过了临床试验的检验：


# J* A% ?, |+ a( p1、《Total pineal endocrine substitution therapy (TPEST) as a new neuroendocrine palliative treatment of untreatable metastatic solid tumor patients: a phase II study》
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“Methods: The study included 14 metastatic solid tumor patients, who had failed to respond to the conventional anticancer therapies. The pineal indoles were given orally according to a schedule elaborated in an attempt to reproduce their physiological circadian secretion during the daily photoperiod. MLT was given at 20 mg/day during the night, whereas the other indoles were given at 1 mg/day, by administering 5-MIA in the morning, 5-MTP at noon and 5-MTT in the afternoon.
! q! L6 A; P3 w. {5 D1 \* dResults: A disease-control was achieved in 9/14 (64%) patients, consisting of partial response (PR) in one patient and stable disease (SD) in the other 8 patients. The median time of disease-control (PR + SD) was 6 months (range: 4-10).”

无药可用的晚期实体瘤患者，在不用化疗药靶向药这些常规抗癌治疗的情况下，根据昼夜节律时辰给药每天就吃了点褪黑素之类的东西，实现了64%的疾病控制率，控制中位期6个月。
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这个临床试验结果让人惊叹。


2、《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.”

前面讲过IL-2+褪黑素免疫治疗的几个临床试验疾病控制率在55-60%左右；这个临床试验在IL-2+褪黑素的基础上联用了另外一种松果体吲哚5-methoxytryptophol，疾病控制率上升到了71%。
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/ @( H+ t* o5 v8 Z. h" K! ^' ~3、《Immunomodulatory properties of a pineal indole hormone other than melatonin, the 5-methoxytryptophol》

$ w9 [( w+ d: E  j) d7 `“Several experiments have suggested that the pineal gland has an antitumor immunomodulatory action. Melatonin (MLT), the best known pineal hormone, has been shown to stimulate anticancer immune defenses during the night, corresponding to the period of its maximum blood levels, whereas it has no effect during the light phase of the day. At present, no study has been performed to investigate possible immunomodulating properties of other pineal indoles, such as 5-methoxytryptophol (5-MTL), whose circadian secretion would be opposite with respect to that of MLT, since it reaches its highest levels during the light phase of the day. In an attempt to analyze possible effects of 5-MTL on anticancer immunity, we have evaluated the action of 5-MTL (1 mg/ day orally at noon for 5 days) in 10 healthy volunteers on the two fundamental suppressive and immunostimulatory cytokines, consisting of IL-6 and IL-2, respectively. Serum levels of IL-2 and IL-6 were measured by an immunoradiometric method. Mean serum concentrations of IL-2 significantly increased on 5-MTL therapy, whereas those of IL-6 significantly decreased in response to 5-MTL. This preliminary study would suggest that the less known pineal indole 5-MTL, as well as MLT, has important immunomodulatory effects on cytokine secretions, including those involved in the antitumor immune response, by further confirming the essential role of the pineal as a central regulation of biological response modifier system. Several pineal alterations have been described in advanced cancer patients. According to the results of this study, the simultaneous administration of MLT during the dark phase and of 5-MTL during the light period of the day could further contribute to correcting pineal functions and to pilot the host anticancer immune reaction in an antitumor direction with respect to MLT alone.”

用了5-methoxytryptophol后，IL-2上升了，IL-6降低了。
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