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Abrogation of the negative influence of opioids on IL-2 immunotherapy of renal cell cancer by melatonin

Published on Thursday, 17 January 2019

Abstract

IL-2 immunotherapy has been proven to be effective in the treatment of metastatic renal cell cancer (RCC). However, several drugs commonly used in the palliative therapy of cancer may potentially influence IL-2 efficacy, since the anticancer immunity has appeared to depend on complex interactions between immune system and psychoneuroimmunomodulation.

In particular, experimental studies and preliminary clinical investigations have shown that the opioid substances, namely morphine, may suppress the anticancer immunity and the efficacy of IL-2 itself. In contrast, other neuroactive substances, in particular the pineal hormone melatonin (MLT), have been proven to stimulate the immune response, including the anticancer immunity, and to abrogate opioid-induced immunosuppression.

On this basis, a study was planned to evaluate the effect of a concomitant MLT administration on the efficacy of IL-2 immunotherapy in advanced cancer patients chronically treated with morphine for cancer-related pain.

The study was carried out in 30 metastatic RCC patients under chronic therapy with morphine at oral doses ranging from 60 to 120 mg/day.

Patients were randomized to receive morphine alone or morphine plus MLT (20 mg/day orally in the evening).

The immunotherapeutic cycle consisted of IL-2 subcutaneous administration at a dose of 6 million IU/day for 6 days/week for 4 consecutive weeks. In nonprogressing patients, a second cycle was planned after a 21-day rest period.

The percent of partial responses achieved in patients treated with morphine alone was significantly lower than that observed in patients concomitantly treated with MLT (1/16 vs. 4/14, p<0.05).

Moreover, the 3-year percent of survival was significantly higher in patients concomitantly treated with MLT (p<0.01).

In contrast, no diminished analgesic efficacy of morphine occurred in patients concomitantly treated with MLT.

This preliminary study seems to suggest that the negative influence of morphine therapy for cancer-related pain on the clinical efficacy of IL-2 cancer immunotherapy may be abrogated by the concomitant administration of the immunomodulating pineal neurohormone MLT.

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About tis publication.

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);

- Neuroblastoma: Complete objective response to biological treatment;