We initially determined the sensitivity of hepatoma 7288CTC to the oncostatic effects of pharmacological doses of melatonin (50 to 200 (g) injected S.C. into tumor-bearing rats, maintained on a 12L:12D light:dark cycle, every afternoon one to two hours prior to lights off (PM). Injections with melatonin or vehicle began one week prior to tumor implantation and continued until the end of the experiment three to four weeks later. Melatonin treatment was effective in delaying the appearance and suppressing the growth of hepatoma 7288CTC at all doses tested. Furthermore, the tumor uptake, content and release of linoleic acid, total fatty acids and 13-HODE, respectively, was suppressed in animals receiving PM melatonin therapy in a dose-dependent manner. Interestingly, in a study in which melatonin (200 (g to 1mg) was injected in the morning (AM) two to three hours following lights on, there was no effect on tumor growth or linoleic acid uptake and metabolism (6-8; unpublished results). However, unlike animals maintained in diurnal lighting, tumor growth and linoleic acid uptake and metabolism in rats maintained under constant light conditions were equally inhibited regardless of whether melatonin was injected during either the subjective AM or PM (unpublished results). We concluded from these results that melatonin's inhibitory effect on the growth of and linoleic acid uptake and metabolism by hepatoma 7288CTC was both dose- and circadian-time dependent. It is unclear at this point what mechanism is responsible for the apparent diurnal rhythm of tumor sensitivity to mela-tonin in rats maintained on diurnal lighting. However, the elimination of this sensitivity rhythm of hepatoma 7288CTC to melatonin in constant light strongly suggests that the normal endogenous melatonin rhythm itself may drive this tumor rhythm under diurnal lighting conditions.
We next turned our attention to the issue of whether the physiological nocturnal melatonin signal itself exerted an oncostatic effect on tumor growth and metabolism. Previous studies in vivo had demonstrated that pinealectomy or constant light exposure increased the incidence of carcinogen-induced mammary cancer in rats while in vitro studies have shown that physiological concentrations of melatonin inhibit cancer cell proliferation (1). We approached this question in vivo by extinguishing the nocturnal melatonin peak by either pinealectomy or exposure of tumor-bearing animals to either constant bright light or a 12L:12D lighting regimen in which the dark phase was "contaminated" by low intensity light (0.2 lux) (14). In each of these scenarios, the onset of palpable tumors was substantially advanced and the tumor growth rate was accelerated by two-fold over that of 12L:12D intact or sham-pinealectomized controls. Additionally, the tumor uptake of linoleic acid and its conversion to 13-HODE were also markedly elevated in these animals providing strong evidence that the physiological nocturnal melatonin signal is critical for restraining the growth of these tumors, presumably by inhibiting linoleic acid uptake and metabolism to 13-HODE.
We reasoned that if the circadian melatonin signal itself is a critical inhibitory regulator of tumor growth and metabolism as well as a driving force for a diurnal rhythm of tumor sensitivity to exogenous melatonin, then hepatoma 7288CTC should evince a circadian rhythm of linoleic acid uptake and metabolism that is the "mirror-image" of the melatonin rhythm. Arteriovenous difference measurements made across tumors at six different circadian time points showed that linoleic acid uptake and oxidation to 13-HODE were highest during the light phase when circulating melatonin levels were low and lowest when melatonin levels were at their peak. This circadian rhythm of tumor metabolism was completely eliminated by pinealectomy (8; unpublished results). These results make a convincing argument for a melatonin-driven circadian rhythm of linoleic acid uptake and metabolism.
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