Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms

doi:10.1016/j.patbio.2006.12.025

Pathologie Biologie

Volume 55, Issues 3–4, April–May 2007, Pages 201-204

https://doi.org/10.1016/j.patbio.2006.12.025 Get rights and content

Abstract

It is known since many years that the pineal hormone melatonin (MLT) may play anticancer activity through several mechanisms, including antiproliferative and immunostimulating effects. Moreover, it exerts an important antioxidant action. Therefore, MLT could be useful in the treatment of human neoplasms, either alone or in association with chemotherapy. The present study was performed to evaluate the influence of a concomitant MLT administration on efficacy and toxicity of several chemotherapeutic combinations in metastatic solid tumor patients, suffering from non-small cell lung cancer (NSCLC) or gastrointestinal tumors. The study included 370 patients who were randomized to receive chemotherapy alone or chemotherapy plus MLT (20 mg/day orally in the evening every day). NSCLC patients received cisplatin (CDDP) plus etoposide or CDDP plus gemcitabine. Colorectal cancer patients were treated with oxaliplatin plus 5-fluorouracil (5-FU), or weekly CPT-11 or 5-FU and folates (FA). Finally, gastric cancer patients received CDDP, epirubicin, 5-FU and FA or weekly 5-FU plus FA. The overall tumor regression rate achieved in patients concomitantly treated with MLT was significantly higher than that found in those treated with chemotherapy alone. Moreover, the 2-year survival rate was significantly higher in patients concomitantly treated with MLT. These results confirm in human the anticancer therapeutic properties of the pineal hormone MLT, which may enhance the efficacy of the standard anticancer chemotherapies.

Résumé

Depuis plusieurs années, l'hormone pinéale mélatonine (MLT) est connue pour son activité antitumorale, via plusieurs mécanismes dont des effets antiprolifératifs et immunostimulants. De surcroît, cette hormone exerce une importante action antioxydante. C'est pourquoi la MLT pourrait être indiquée dans le traitement de la néoplasie humaine, soit seule, soit en association avec la chimiothérapie. La présente étude était réalisée pour évaluer l'influence d'une administration concomitante de MLT sur l'efficacité et la toxicité de plusieurs combinaisons chimiothérapeutiques chez des patients présentant des tumeurs solides métastatiques : des tumeurs bronchiques non à petites cellules (NSCLC) ou des cancers gastro-intestinaux. Trois cent soixante-dix patients inclus dans cette étude étaient randomisés pour recevoir soit une chimiothérapie seule, soit une chimiothérapie associée à de la MLT (20 mg/jour per os, le soir). Les patients avec un NSCLC recevaient du cisplatine (CDDP) plus de l'étoposide ou bien du CDDP plus de la gemcitabine. Pour les cancers colorectaux, les patients étaient traités à l'aide d'oxaliplatine plus du 5-fluorouracile (5-FU), ou de manière hebdomadaire du CPT-11 ou du 5-FU et de l'acide folinique (FA). Enfin, les patients avec un cancer gastrique recevaient du CDDP, de l'épirubicine, du 5-FU + FA, ou hebdomadairement du 5-FU + FA. Le taux de régression tumorale global obtenu chez les patients traités concomitamment avec la MLT était significativement supérieur à celui observé chez les patients traités par chimiothérapie seule. De plus, le taux de survie à deux ans était significativement plus élevé en cas de traitement associant chimiothérapie et MLT. Ces résultats confirment, chez l'homme, les propriétés thérapeutiques antitumorales de l'hormone pinéale MLT, en amplifiant l'efficacité des chimiothérapies standard contre le cancer.

Introduction

The pineal hormone melatonin (MLT), mainly released during the dark period of the day according to a well defined light/dark circadian rhythm, is the most investigated natural anticancer endocrine agent [1], which is involved in mediating the influence of the psychoneuroendocrine status on cancer development and on the immune functions. MLT exerts anticancer activity at least through three mechanisms [2]:

●
direct cytostatic or cytotoxic action by inducing the apoptotic processes in cancer cells expressing MLT receptors (MLT-R);
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stimulation of the antitumor immune response, namely by promoting IL-2 release from TH1 lymphocytes, which may express MLT-R, and by enhancing IL-12 production by dendritic cells in response to IL-2;
●
modulation of oncogene expression, with differentiating activity on cancer cells mainly on endocrine receptor expression, with a consequent lower biological malignancy.

Moreover, it has been recently demonstrated that MLT may counteract the activation of EGF-receptor (EGF-R) [3], whose expression plays an important role in determining the biological malignancy of cancer cells and their metastatic capacity. Finally, MLT is one of the most potent antioxidant agents [4], with a following potential protective action against chemotherapy-induced toxicity, which is due at least in part to an enhanced free-radical production. In particular, MLT has been proven to prevent chemotherapy- and radiotherapy-induced lymphocyte damage [4], thrombocytopenia, neurotoxicity and cardiotoxicity in experimental conditions. Because of the fundamental role of lymphocytes in the anticancer immunity [5], whose efficacy may influence the clinical course of the neoplastic disease, MLT-induced prevention of lymphocyte damage could prolong the survival time of chemotherapy-treated cancer patients. In fact, the lack of a clear correlation between objective tumor regression in response to chemotherapy and survival time in several tumors, namely lung cancer and gastrointestinal neoplasms, would mainly be due to the immunosuppressive effect of most anticancer drugs. In addition, the antioxidant agents have proven to amplify the cytotoxic potency of chemotherapy [6]. Therefore, MLT could enhance the efficacy of chemotherapy in term of both tumor regression rate and survival time. In fact, preliminary clinical studies in cancer patients would demonstrate the benefits of MLT in association with cancer chemotherapy [7]. Finally, it has to be taken into consideration that the physiological light/dark rhythm of MLT is often absent in advanced cancer patients [1]. Then, because of the fundamental role of MLT in regulating the chronobiological rhythms [1], the exogenous administration of MLT during the dark period to establish its endogenous circadian rhythm would constitute the most easy and important strategy of a chronomodulatory approach in the treatment of human neoplasms. On this basis, a randomized study was planned to evaluate the influence of a concomitant MLT administration on the efficacy and toxicity of various chemotherapeutic combinations in the treatment of metastatic solid neoplasm, whose treatment has still to be improved, such as non-small cell lung cancer (NSCLC) and gastrointestinal tract tumors. The end-point of the study was the evaluation of tumor regression rate and the 2-year survival.

Section snippets

Materials and methods

The study included 370 consecutive cancer patients. Eligibility criteria were as follow: histologically proven metastatic NSCLC or gastrointestinal neoplasms, measurable lesions, no more that one previous chemotherapeutic line, no brain metastases and no double tumor. NSCLC patients were treated with cisplatin (CDDP) plus etoposide (VP-16) or with CDDP plus gemcitabine (GEM); colorectal cancer patients received oxaliplatin (OXA) plus 5-fluorouracil (5-FU) and folates (FA), or 5-FU and FA or

Results

The clinical results are shown in Table 1. The two groups of patients were well balanced for the main prognostic variables, including tumor hystotype and sites of disease. The clinical response consisted of complete responses (CR) in 12 and partial responses (PR) in 56 patients treated with chemotherapy plus MLT, and of CR in five and PR in 32 patients, who received chemotherapy alone. Then, the response rate (CR + PR) achieved in patients concomitantly treated with MLT was significantly higher

Discussion

According to the results obtained in experimental conditions [1], [4], [7], this study confirms that the concomitant administration of the natural anticancer agent MLT may enhance the efficacy of cancer chemotherapy and reduce its toxicity. These results are not surprising since all benefits induced by MLT may be explained on the basis of well defined biological mechanisms, by depending on the oncostatic, immunomodulating and antioxidant properties of MLT itself. In addition, the enhanced

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Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasmsLa biochimiothérapie avec les chimiothérapies standard et l'hormone pinéale mélatonine dans le traitement de solides néoplasies avancées

Abstract

Résumé

Introduction

Section snippets

Materials and methods

Results

Discussion

J. Pain Symptom Manage.

Melatonin in humans

N. Engl. J. Med.

Melatonin: a rediscovered antitumor hormone?

Cancer Invest.