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Identification of Linoleic and Arachidonic Acids as the Factors in Hyperlipemic Blood That Increase [³H]Thymidine Incorporation in Hepatoma 7288CTC Perfused in Situ¹

Laboratory for Cancer Research, Bassett Institute for Medical Research, The Mary Imogene Bassett Hospital, Cooperstown, New York 13326

Tumor growth and the incorporation of [³H]thymidine into tumor DNA in vivo are increased about 3 times in adult rats (greater than 250 g) after 1 to 2 days of starvation or the induction of diabetes with streptozotocin. These tumor growth responses require hyperlipemia and are reversed by refeeding or insulin treatment, respectively. They do not occur in young tumor-bearing rats (less than about 150 g) that lack appreciable fat stores. A direct relationship between the increased rates of both [³H]thymidine incorporation and tumor growth and host hyperlipemia suggests that tumor cell renewal in vivo in fed rats is limited by substances that are present in hyperlipemic blood.

In this study we used a procedure for perfusion of solid tumors in situ to measure the sensitivity of tumor [³H]thymidine incorporation to hyperlipemic blood and to identify the rate-limiting substances. Tissue-isolated Morris hepatomas (7288CTC) growing in young or adult Buffalo rats were perfused with blood from donor rats. Hyperlipemic blood for perfusion was obtained from 2-day starved tumor-bearing (Buffalo) or non-tumor-bearing (Buffalo or Lewis) rats. At the end of the perfusions the tumors were labeled with a pulse of [³H]thymidine (2 µCi/g estimated tumor wet weight). [³H]Thymidine incorporation in tumors growing in fed adult rats was increased from 80 ± 5 (SD) dpm/µg DNA at zero time (before perfusion) to 209 ± 9 dpm/µg DNA (n = 3) after perfusion for 3 h. Tumors growing in fed or starved young rats showed similar responses, and hyperlipemic blood from non-tumor-bearing rats was as effective as hyperlipemic blood from tumor-bearing rats. Perfusion of tumors growing in starved rats with normolipemic blood from fed adult rats decreased [³H]thymidine incorporation from 211 ± 13 dpm/µg DNA before perfusion to 68 ± 9 dpm/µg DNA (n = 3) after perfusion for 3 h.

Cells, plasma, and plasma subfractions from hyperlipemic blood were reconstituted to whole blood using plasma, cells, and whole blood, respectively, from fed rats and the mixtures were perfused into tumors growing in fed adult rats. Mixtures containing hyperlipemic plasma, lipid extracts (ethanol:acetone, 1:1) of hyperlipemic plasma, or albumin from hyperlipemic plasma increased tumor [³H]thymidine incorporation. Free fatty acid concentrations were increased about five times in hyperlipemic plasma and perfusion of tumors with normolipemic blood containing added linoleic and arachidonic acids increased [³H]thymidine incorporation. Blood mixtures containing palmitic, stearic, and oleic acids were inactive. We conclude that linoleic and arachidonic acids are rate limiting for [³H]thymidine incorporation in tumors growing in young and adult rats.

¹ This investigation was supported by USPHS Grant CA 27809, awarded by the National Cancer Institute, Department of Health and Human Serives, and by the Stephen Carlton Clark Research Fund of The Mary Imogene Bassett Hospital.

² To whom requests for reprints should be addressed.

Received 7/ 2/87. Revised 12/ 8/87. Revised 2/17/88. Accepted 2/25/88.

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