Oncostatic activity of pineal neuroendocrine treatment with the pineal indoles melatonin and 5-methoxytryptamine in untreatable metastatic cancer patients progressing on melatonin alone

ArticleinNeuro endocrinology letters 21(4):319-323 · February 2000with7 Reads
Source: PubMed
OBJECTIVE: The recent advances in psycho-neuro-endocrino-immunology have demonstrated the existence of several endogenous neuroendocrine substances, capable of affecting both tumor growth and host anticancer immune defenses. The pineal gland would represent one of the most important organs releasing antiproliferative and immunostimulating substances, the most known of them is melatonin (MLT). However, MLT would not be the only pineal indole provided by antitumor activity. Other pineal indoles, namely 5-methoxytryptamine (5-MTT), would play antitumor effects, by either inhibiting cancer cell proliferation or stimulating the anticancer immunity. Preliminary data have shown that MLT may deserve antitumor activity in the treatment of human neoplasms, whereas at present there are no clear data about 5-MTT. In an attempt to obtain some preliminary data about the anticancer properties of 5-MTT in humans, we have evaluated the efficacy of MLT plus 5-MTT in untreatable advanced cancer patients progressing on MLT alone. METHODS: The study included 73 untreatable advanced solid tumor patients, who had progressed after two months of MLT therapy alone. According to tumor histotype, patients were randomized to receive MLT alone (20 mg/day orally in the evening) or MLT plus 5-MTT (1 mg at noon orally), every day for at least two months. The clinical response was evaluated according to WHO criteria. RESULTS: A partial response (PR) occurred in two patients treated with MLT + 5-MTT and in none of the patients receiving MLT alone. A stable disease (SD) was achieved in only 2/37 patients on MLT therapy alone, and in 8/36 patients receiving MLT plus 5-MTT. Therefore, the percent of non-progressing patients (SD + PR) obtained with MLT plus 5-MTT was significantly higher than that obtained with MLT alone. Moreover, the relief of asthenia and depressant symptoms was significantly higher in patients concomitantly treated with 5-MTT. DISCUSSION: This preliminary study would suggest that the concomitant administration of the less known pineal indole 5-MTT, also provided by antiproliferative and immunomodulating effects, may further amplify the oncostatic activity of the pineal hormone MLT in the palliative and curative therapy of advanced untreatable human solid neoplasms.
    • "Thus, this compound regulates the biological rhythms and the reproductive behavior of several animal species, including humans. In addition, 5-MTX is a matter of high clinical relevance since it has been described as pro-or antigonadotropic hormone according to species[Balemans et al., 1977;Sackman et al., 1977], as a potent supplement in the treatment of cancer[Lissoni et al., 1997;Lissoni et al., 2000], as antioxidant[García et al., 2000;Rodriguez-Naranjo et al., 2012]and as immunomodulatory agent[Lissoni et al., 1996]. However, there is no data to date regarding its role in bone metabolism. "
    [Show abstract] [Hide abstract] ABSTRACT: The present study investigates the direct action of 5-methoxytryptophol (5-MTX) in both MC3T3-E1 and RAW264.7 cells and compares it with melatonin (MEL), another 5-methoxyindol known to play a significant role on bone metabolism. We first screened increasing doses of both 5-MTX and MEL to determine their effect on metabolic activity and viability of preosteoblastic MC3T3-E1 cells. The optimal dose was used to determine its effect on differentiation of MC3T3-E1 cells and preosteoclastic RAW264.7 cells. Finally, we investigated the mechanism of action by adding the melatonin receptor antagonist luzindole (LUZ) and detecting the immunostaining of phospho-ERK.In MC3T3-E1 cells, most of the 5-MTX doses reduced slightly the metabolic activity of osteoblasts compared with the control, while MEL only decreased it for the highest dose (2.5 mM). As regards to cytotoxicity, low doses (0.001–0.1 mM) of both indoles showed a protective effect on osteoblasts, while the highest dose of MEL showed a higher cytotoxicity than the 5-MTX one. After 14 days of cell culture, Rankl mRNA levels were decreased, especially for 5-MTX. 5-MTX also induced a higher osteocalcin secretion and mineralization capacity than MEL. In RAW264.7 cells, 5-MTX decreased the number of osteoclast formed and its activity whereas MEL did not affect significantly the number of multinucleated TRAP-positive cells formed and showed a lower activity. Finally, MEL and 5-MTX promoted activation of the ERK1/2 pathway through the phosphorylation of ERK, while LUZ addition suppressed this effect.In conclusion, the present study demonstrates a new role of 5-MTX inhibiting osteoclastogenesis and promoting osteoblast differentiation. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
    Article · Oct 2014
    • "If melatonin has a treatment effect on depression, it must also be evaluated whether melatonin only has an effect in those patients who exhibit a clear chronobiological disturbance in their depression (Boyce and Hopwood, 2013; Malhi and Kuiper, 2013). Furthermore, whether melatonin could have a possible synergistic effect when given together with other antidepressants (HirschRodriguez et al., 2007), or other treatments such as bright light (Riemersma-van der Lek et al., 2008), tamoxifen (Lissoni et al., 1995), 5-methoxytryptamine (Lissoni et al., 2000) or buspirone (Fava et al., 2012) and thereby be used as an add-on must be investigated. In view of the longer half-life and much higher potencies of the different melatonin agonists, such as ramelteon, future studies are also warranted with melatonin in higher doses before the relative effect of melatonin can be clarified (Cardinali et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Circadian- and sleep disturbances may be central for understanding the pathophysiology and treatment of depression. The effect of melatonin on depression/depressive symptoms has been investigated previously. This systematic review assesses the current evidence of a therapeutic- and prophylactic effect of melatonin in adult patients against depression or depressive symptoms. A search was performed in The Cochrane Library, PubMed, EMBASE and PsycINFO for published trials on November 14th 2013. Inclusion criteria were English language, RCTs or crossover trials. Our outcome was measurement of depression/depressive symptoms with a validated clinician-administered or self-rating questionnaire. PRISMA recommendations were followed and the Cochrane risk-of-bias tool used. Ten studies in 486 patients were included in the final qualitative synthesis and four studies, 148 patients, were included in two meta-analyses. Melatonin doses varied from 0.5–6 mg daily and the length of follow-up varied from 2 weeks to 3.5 years. Three studies were done on patients without depression at inclusion, two studies in patients with depression and five studies included a mixture. Six studies showed an improvement in depression scores in both the melatonin and placebo groups but there was no significant difference. One study showed a significant prophylactic effect and another found a significant treatment effect on depression with melatonin compared to placebo. The two meta-analyses did not show any significant effect of melatonin. No serious adverse events were reported. Although some studies were positive, there was no clear evidence of a therapeutic- or prophylactic effect of melatonin against depression or depressive symptoms.
    Full-text · Article · Aug 2014
    • "Various studies have shown that MLT has marked oncostatic properties that can reduce the promotion or progression of the tumor. Various authors have demonstrated that the antiproliferative properties of MLT take place through inhibition/blocking of the cell cycle333435363738. This is confirmed by clinical studies in which, according to Luigi Di Bella, MLT alone cannot heal a tumor but without MLT it is difficult to heal any tumor. "
    [Show abstract] [Hide abstract] ABSTRACT: Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases.
    Full-text · Article · Feb 2013
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