Human cancer xenograft perfusion in situ in rats: A new perfusion system that minimizes delivery time and maintains normal tissue physiology and responsiveness to growth-inhibitory agents

We developed an artificial lung and catheter system for perfusing tissue-isolated tumors in situ that dramatically minimizes perfusate delivery time. Our investigations demonstrated that the circadian neurohormone melatonin (MLT), eicosapentaenoic acid (EPA), and conjugated linoleic acid (CLA) inhibit growth and metabolism in several rodent and human tumors. These anticancer agents function in a receptor-mediated manner to suppress tumor uptake of linoleic acid (LA), the principal tumor growth-promoting fatty acid, and its conversion to the mitogenic agent 13-hydroxyoctadecadienoic acid (13-HODE). Using this perfusion system and MCF-7 human breast xenografts, we examined the efficacy and timing of perfusate delivery to tumors. Tumors were perfused with rat donor blood to establish baseline LA uptake values; after 36 min of perfusion, we supplemented the perfusate with MLT, EPA, or CLA and collected arteriovenous whole-blood samples over 5-min intervals for a total perfusion period of 70 min. Arterial blood pH, pO2, and pCO2 (mean ± 1 standard deviation) were 7.46 ± 0.01, 155.5 ± 2.4, and 33.5 ± 0.9 mm Hg, and venous blood pH, pO2, and pCO2 were 7.30 ± 0.02, 33.7 ± 1.9, and 59.8 ± 1.9 mm Hg, respectively; none of these values varied during the perfusions. Tumor LA uptake and 13-HODE production were 1.06 ± 0.28 μg/min/g and 1.38 ± 0.02 ng/min/g, respectively, and were completely suppressed within 5 min after delivery of anticancer agents to the tissue. This new system provides rapid perfusate delivery for use with both normal and neoplastic tissues while maintaining normal physiologic tissue parameters.