Este trabalho apresenta uma revisão da literatura das três últimas décadas sobre o papel da melatonina (MEL) na etiopatogenia e no tratamento do câncer. Os principais mecanismos de ação da MEL envolvem a regulação imunológica, efeitos bioquímicos e metabólicos. São relatados estudos in vitro e in vivo, inclusive em humanos com neoplasias malignas avançadas e/ou metastáticas, como tumores de mama, próstata, pulmonar, gástrico, hepático, ovariano e de intestino. Duas ações benéficas da MEL no tratamento do câncer são aparentemente importantes: a oncostática e a protetora contra os efeitos adversos da quimioterapia (mielossupressores, neurotóxicos e hematológicos). A MEL também passou a ser utilizada em uma nova modalidade de terapia oncológica, a imunoterapia, na década de 1990 para tratar pacientes com câncer de pulmão de células não-pequenas.

Previous studies have shown that the pineal gland of Roman high avoidance (RHA/Verh) rats is larger than that of Roman low avoidance rats (RLA/Verh). In the present study measurement of enzyme activities (serotonin-N-acetyl-transferase, hydroxyindole-O-methyltransferase) revealed that pineals of RHA/Verh rats are twice as active in melatonin production than pineals of RLA/Verh rats. Indoleamine content was also higher in RHA/Verh rats, whereas noradrenaline content was the same in both lines. When values were expressed per mg protein, these differences disappeared except for N-acetyl-serotonin and noradrenaline which were higher or lower in RHA/Verh rats, respectively. Both lines had higher serum levels of melatonin during the dark phase than during the light phase. However, RHA/Verh rats had increased serum levels as compared to RLA/Verh rats during both day and night. Morphometric analysis of the deep and superficial part of the pineal complex revealed, that the volumes of both parts are enlarged in RHA/Verh rats. Electron microscopic studies of pineals collected during day- and nighttime showed higher numbers of synaptic ribbons per unit area in pineals of RHA/Verh rats. In pineals collected during June synaptic ribbons displayed a day/night rhythm in RHA/Verh rats only, whereas in glands of both lines collected during November no daily changes were found. These results show that closely related but divergently selected rat lines may differ in pineal ultrastructure and pineal function.

To elucidate the role of protein synthesis in the nocturnal increase of synaptic ribbons in the rat pineal gland, actinomycin-D, which inhibits transcription, and cycloheximide, an inhibitor of translation, were used. To assure that the drugs were effective and to relate morphological changes to pineal biosynthetic phenomena, the activity of N-acetyltransferase and levels of pineal indoleamine were measured. Results of in-vivo, short-term and long-term treatment with either drug suggest that transcription of proteins related to synaptic ribbon formation occurs during the first half of the light phase, whereas translation takes place during the first few hours of the dark phase. In contrast, proteins involved in enhanced melatonin synthesis are transcribed and translated during the first few hours of the dark phase. In vitro, preincubation with inhibitors of protein synthesis abolished the increase in the numbers of synaptic ribbons after stimulation with dibutyryl-adenosine-cyclic-monophosphate, indicating that the results of the in-vivo experiments are due to an interaction of the drugs with the pineal gland itself. The present study shows that, although in the rat pineal enhanced melatonin synthesis and increased numbers of synaptic ribbons occur at the same time, transcription of proteins involved in both rhythms is temporally separated.

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