A Preliminary Study on the Anticancer Properties of Oxytocin: A Neuroendocrine Regimen with Oxytocin, Antitumor Pineal Indoles, and Cannabidiol in Untreatable Advanced Cancer Patients Progressing on Pineal Indoles and Cannabidiol Alone

The recent discovery of several endogenous and exogenous anticancer non-toxic molecules has allowed the possibility to administer potential anticancer curative regimens also in patients, who would be generally considered as eligible for the only palliative therapy. Within the anticancer molecules of the human body, it has been shown that the pineal indole hormones and the endocannabinoid agents may play an anticancer activity against most tumor histotypes through several mechanisms, including cytotoxic, anti-angiogenic and immunostimulatory effect on the anticancer immunity, and to prolong the survival time in advanced cancer patients eligible for the only supportive care. In fact, cancer progression has appeared to be associated with a progressive decline in the functionless of the pineal gland and endocannabinoid system. The endocannabinoid brain activity may be enhanced by the non-psychoactive principle A Preliminary Study on the Anticancer Properties of Oxytocin: A Neuroendocrine Regimen with Oxytocin, Antitumor Pineal Indoles, and Cannabidiol in Untreatable Advanced Cancer Patients Progressing on Pineal Indoles and Cannabidiol Alone. Oncogen 2(4): 18. system [9] and probably to a dimished OXY secretion [13]. Then, the progressive correction of these major cancer-related neuroendocrine deficiencies through an exogenous administration could improve the control of cancer growth. In fact, some preliminary clinical studies have already demonstrated the possibility to enhance the survival time in a considerable number of advanced cancer patients eligible for the only palliative therapy, and also to achieve some tumor regressions even though in a very low percentage of untreatable disseminated cancer patients, through the administration of high-dose pineal indole hormones MLT and 5-MTT [17]. Further studies have shown the possibility to achieve a greater increase in the survival time of untreatable (5-MTT) were given orally at 100 mg/day in the dark period, and at 10 mg/day in the light period, respectively. CBD was also given orally at 10 mg twice/day. Finally, OXY was given orally at 2 mg twice/day in a gastroprotected form. A stable disease (SD) was achieved in 8/14 (57%) patients (gynecologic tumors: 5; TNBC: 2; GBM: 1), whereas 6 patients had a progressive disease (PD). The percentage of 1-year survival obtained in patients with SD was significantly higher than that found in patients with PD. Moreover, a clear improvement in mood, social relationships and pleasure perception was observed in 9/14 (64%) patients under OXY administration. These preliminary results would furtherly confirm the possibility to obtain a control of the neoplastic growth also in advanced cancer patients eligible for the only supportive care alone by simply correcting the main cancer- progression-related endogenous neuroendocrine deficiencies, including pineal system and OXY secretion.


INTRODUCTION
The recent advances in the knowledge of the neuroendocrine and immunological mechanisms responsible for cancer onset and development have allowed the discovery of the existence of several natural anticancer non-toxic molecules, either in plants or in the same human body, with the following possibility to offer new potential anticancer regimens with natural anticancer agents to cancer patients with disseminated neoplasms eligible for the only best supportive care (BSC) alone, even though not completely standardized, in an attempt to improve not only their quality of life, but the survival time by improving the efficacy of the anticancer immunity [1][2][3]. Most of the endogenous anticancer molecules are produced by the pineal gland, whose anticancer activity is known since many years, by representing one of the main organs responsible for the natural anticancer resistance of living organisms [4]. The main anticancer hormones produced by the pineal gland are the indoles melatonin (MLT) [5] and 5-methoxytryptamine (5-MTT) [6], and several betacarbolines, the most investigated of them is the 6-methoxy-1,2,3,4-tetrahydro-beta-carboline [7], the so-called pinealine.
The pineal hormones play an anticancer activity due to several mechanisms, including a direct cytostatic cytotoxic activity, an immunostimulating effect on the T lymphocytemediated anticancer immunity, and an anti-angiogenic action [8]. The endogenous cannabinoids, the most important of them are consisting of arachidonyl-ethanol-amide (AEA) and 2-arachidonyl-glycerol (2-AG), have also appeared to exert an anticancer action on several cancer cell lines through a direct anti-proliferative and anti-angiogenic action [9], as well as by counteracting macrophage-mediated chronic inflammatory response, which has been proven to promote cancer dissemination [10]. The endogenous cannabinoids are destroied by the enzyme fatty acid amide hydrolase (FAAH), then the administration of FAAH inhibitors may allow an increase in cannabinoid endogenous content [11]. The nonpsychoactive principle of Cannabis indica cannabidiol (CBD), which is not a cannabinoid receptor agonist, has appeared to inhibit FAAH activity [9], then its administration could allow an increase in the endogenous content of both AEA and 2-AG, with a following enhancement in the potency of the natural resistance against cancer growth. A potent anticancer activity is also played by the cardiac hormone atrial natriuretic peptide (ANP) because of its anti-proliferative, anti-angiogenic, antiinflammatory and immunostimulatory effects [12], even though its too short half-life at present does not permit its clinical therapeutic use. Finally, the neurohypophyseal hormone oxytocin (OXY) has also appeared to be an anticancer molecule, at least against breast cancer, brain tumors, and gynecologyc neoplasms [13], due to a direct antiproliferative action [14] and to an immunostimulatory activity on IL-2-dependent anticancer immunity [15], whereas controversial results have been reported for prostate cancer and germinal tumors. According to the recent advances in the psychoneuroendocrinoimmunology (PNEI) of cancer, at present it is known that cancer progression and cancerrelated immunosuppression may be due at least in part to a pineal endocrine deficiency [16], to a failure of the endocannabinoid system [9] and probably to a dimished OXY secretion [13]. Then, the progressive correction of these lymphocyte-to-monocyte ratio (LMR), whose diminished value has appeared to predict a less favourable prognosis in most cancer histotypes [19], since it has been proven to synthetically reflect the equilibrium between the anticancer immunity mediated by TH1 and cytotoxic T lymphocytes and the chronic inflammatory status-related immunosuppression of the anticancer immunity, mediated by the macrophage and regulatory T lymphocyte (T reg) systems. Normal values of LMR observed in our laboratory (95% confidence limits) was more than 2.1. Data were statistically evaluated by the chisquare test and the Student's t test, as appropriate.

RESULTS
The clinical results are reported in Table 1. Tumor histotypes were, as follows: TNBC: 4; GBM: 3; ovarian cancer: 3; cervix carcinoma: 2; endometrial adeocarcinoma: 2. No objective tumor regression was seen. However, a stable disease (SD) was obtained in 8/14 (57%), with a median duration of 5 months (range 3-11 months) (GBM: 1; TNBC: 2; ovary: 2; endometrium: 2; uterine cervix: 1), whereas the remaining 6 patients had a progressive disease (PD). Moreover, the percentage of SD was significantly higher in patients, who had obtained a tumor regression or SD in response to the previous same neuroendocrine regimen without OXY than in those who had a PD (6/8 (75%) vs 2/6 (33%), P<0.05). A survival longer than 1 year was achieved in 7/14 (50%) patients, and the percentage of 1-year survival was significantly higher in patients, who obtained a SD than in those who had a PD (6/8 (75%) vs 1/6 (17%), P<0.01). Finally, the percentage of SD was higher in patients with normal pre-treatment values of LMR than in those with abnormally low values prior to therapy (4/6 (67%) vs 4/8 (50%) ), even though the difference was not statistically significant. In any case, LMR mean values observed after 3 months of therapy were significantly higher in patients with SD than in those who had a PD (3.1 +/-0.4 vs 1.5 +/-0.3, P<0.05).
No objective or subjective toxicity was observed. In contrast, with respect to the already subjective benefits achieved by pineal hormones plus CBD, consisting of improved quality of sleep, relief of anxiety, asthenia, anorexia, cachexia, and improvement of mood, the further administration of OXY clinically allowed a clear improvement in the affective and emotional relationships and pleasure perception in 9/14 (64%) patients, and the percentage of improvement was significantly higher in patients with SD than in those with PD (7/8 (88%) vs 2/6 (33%), P<0.05).  [19] and stimulating the functionless of mirror neurons [20], whose fundamental role in learning and in promoting the human relationships is well known [21]. Morever, both cannabinoid and MLT may stimulate OXY secretion [22]. Therefore, brain cannabinoid system, pineal gland and OXY-secreting neurohypophysis would constitute a fundamental neurochemical system involved in both social and affective relationships and in natural resistance against cancer development and growth.
In fact, cancer progression has been proven to be associated with a progressive concomitant decline in the functionless of the pineal gland, brain endocannabinoid activity and OXY secretion [5,9,16].

CONCLUSION
Further randomized studies with pineal indoles plus CBD versus their association with OXY will be required to establish whether the concomitant administration of OXY may further increase the disease control and improve the quality of life in advanced cancer patients, for whom no other standard anticancer therapy may be available.