In this model system, a 3-mm cube of Morris rat hepatoma is attached to and grown on the end of a vascular stalk composed of the truncated superficial epigastric artery and vein in the inguinal region of adult male Buffalo rats. The tumor implant and adjacent pedicle are then enclosed in a sterile parafilm envelope containing penicillin. The arterial supply to and venous drainage from the tumor is thus exclusively via the superficial epigastric vessels. nmor attachment to other host tissues or vasculature is blocked by the parafilm envelope. Following replacement of the tumor implant into the inguinal fossa and closure of the skin, the tumor is allowed to grow in a "tissue-isolated" manner. This arrangement allows the cannulation of the epigastric vessels for the direct perfusion of the tumor itself with physiological and/or pharmacological agents and the measurement of arteriovenous differences across the tumor of various biochemical factors and products important in tumor growth and metabolism. All this is accomplished while the tumor is maintained in a physiological state as reflected by the monitoring of blood gases, blood flow, pH, glucose uptake and lactate release (9). We have taken advantage of such a model system to investigate for the first time, using a totally integrative approach, the mechanisms by which melatonin inhibits tumor growth in vivo from the systemic to the biochemical and molecular levels within a chronobiological context.
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