Sauer L A, Dauchy R T
Laboratory for Cancer Research, Bassett Institute for Medical Research, Mary Imogene Bassett Hospital, Cooperstown, New York 13326.
Cancer Res. 1988 Jun 1;48(11):3106-11.
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 microCi/g estimated tumor wet weight). [3H]Thymidine incorporation in tumors growing in fed adult rats was increased from 80 +/- 5 (SD) dpm/micrograms DNA at zero time (before perfusion) to 209 +/- 9 dpm/micrograms 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/micrograms DNA before perfusion to 68 +/- 9 dpm/micrograms 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.(ABSTRACT TRUNCATED AT 400 WORDS)
饥饿1至2天或用链脲佐菌素诱导糖尿病后，成年大鼠（体重超过250克）体内肿瘤生长以及[3H]胸腺嘧啶核苷掺入肿瘤DNA的量增加约3倍。这些肿瘤生长反应需要高脂血症，分别通过重新喂食或胰岛素治疗可使其逆转。在缺乏可观脂肪储备的幼龄荷瘤大鼠（体重约150克以下）中不会出现这些反应。[3H]胸腺嘧啶核苷掺入率和肿瘤生长率的增加与宿主高脂血症之间的直接关系表明，喂食大鼠体内肿瘤细胞的更新受到高脂血症血液中存在的物质的限制。在本研究中，我们采用一种原位灌注实体瘤的方法来测量肿瘤[3H]胸腺嘧啶核苷掺入对高脂血症血液的敏感性，并确定限速物质。将生长在幼龄或成年布法罗大鼠体内的组织分离的莫里斯肝癌（7288CTC）用供体大鼠的血液进行灌注。用于灌注的高脂血症血液取自饥饿2天的荷瘤（布法罗）或无瘤（布法罗或刘易斯）大鼠。灌注结束时，用[3H]胸腺嘧啶核苷脉冲（2微居里/克估计肿瘤湿重）标记肿瘤。喂食的成年大鼠体内生长的肿瘤，在灌注前零时[3H]胸腺嘧啶核苷掺入量为80±5（标准差）dpm/微克DNA,灌注3小时后增加到209±9 dpm/微克DNA（n = 3）。在喂食或饥饿的幼龄大鼠体内生长的肿瘤表现出类似的反应，来自无瘤大鼠的高脂血症血液与来自荷瘤大鼠的高脂血症血液效果相同。用喂食成年大鼠的正常血脂血液灌注饥饿大鼠体内生长的肿瘤，可使[3H]胸腺嘧啶核苷掺入量从灌注前的211±13 dpm/微克DNA降低到灌注3小时后的68±9 dpm/微克DNA（n = 3）。分别使用喂食大鼠的血浆、细胞和全血，将高脂血症血液中的细胞、血浆和血浆亚组分重组成全血，并将混合物灌注到喂食成年大鼠体内生长的肿瘤中。含有高脂血症血浆、高脂血症血浆的脂质提取物（乙醇：丙酮，1:1）或高脂血症血浆白蛋白的混合物可增加肿瘤[3H]胸腺嘧啶核苷掺入。高脂血症血浆中游离脂肪酸浓度增加约5倍，用添加亚油酸和花生四烯酸的正常血脂血液灌注肿瘤可增加[3H]胸腺嘧啶核苷掺入。含有棕榈酸、硬脂酸和油酸的血液混合物无活性。（摘要截断于400字）
