This research is a continuation of studies of tumor growth and metabolism in vivo. A method was developed for growing tissue- isolated tumors in rats and the rat-tumor preparation was used to measure arteriovenous differences across transplantable tumors in situ. Several different tumors were examined and all were found to utilize the major respiratory fuels and substrates needed for growth. Individual substrates were utilized independently from each other and the rates of uptake were directly proportional to the arterial blood concentrations; lactic acid production and uptake from the arterial blood was shown to follow the law of mass action. Mobilization of host fat stores in adult rats by acute starvation or diabetes increased arterial blood concentrations of glycerol, free fatty acids, triglycerides and ketone bodies, increased tumor utilization of these nutrients and increased the rate of tumor DNA synthesis and growth 2 to 4 times. Progress curves measured during onset of the starvation or diabetes showed that increased arterial blood concentrations of these nutrients and increased tumor growth were directly proportional and tightly linked. The tight relationship suggests a requirement for one or more of these substrates in the G1 to S transition and/or in the S phase of the tumor cell cycle. The long term objective for this research is definition of the mechanism(s) for regulation of tumor growth rate in vivo and the pathways for energy production that support the tumor growth. Very little direct information is available on how these processes are controlled and integrated in tumors in the living host. Present results contradict a large body of in vitro biochemical and whole animal nutritional data and reveal large gaps in our understanding.
Specific aims during this grant period are to identify the substance in the blood of starved an diabetic adult rats that is rate-limiting for tumor growth and determine how this substance accelerates the tumor cell cylce. Experiments on uptake and metabolism of this substance will be integrated with ongoing studies of nutrient utilization and energy metabolism. The experiments will be performed using in vivo methods developed in this laboratory and standard in vitro techniques for cell isolation, primary culture and analysis of tumor cell cycle and growth kinetics. This study uses novel techniques to investigate new findings and will extend our understanding of tumor growth and metabolism in vivo.
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