Hursting S D, Switzer B R, French J E, Kari F W
Department of Nutrition, University of North Carolina, Chapel Hill 27599.
Cancer Res. 1993 Jun 15;53(12):2750-7.
A leukemia cell transplant model and both in situ and in vitro bioassays were used to assess the roles of endogenous factors in mediating diet restriction (DR)-induced inhibition of mononuclear cell leukemia (MNCL) in Fischer 344 rats. DR-treated male rats (n = 35), which were fed 75% of ad libitum (AL) intake of NIH-07 open formula diet, had lower transplanted MNCL incidence (54 versus 77%; P = 0.039) with longer latency (P = 0.015) and decreased severity (P = 0.01) than AL-treated rats 12 weeks after inoculation with MNCL cells. Five-day proliferation rates of cultured MNCL (CRNK-16) cells in diffusion chambers implanted in DR-treated rats were 22% less than in AL-treated rats (P = 0.03), indicating that DR-dependent diffusible factor(s) modulate in situ MNCL cell growth. Serum from DR-treated rats supported lower in vitro CRNK-16 cell proliferation rates relative to serum from AL-treated rats. Serum levels of both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) were over 50% lower in DR- versus AL-treated rats. An evaluation of the in vitro cell proliferative activity of a panel of purified factors showed that GH and IGF-1, but not 15 other growth factors, stimulated thymidine incorporation in CRNK-16 cells. Infusion of either GH or IGF-1 via osmotic minipumps restored in situ and in vitro CRNK-16 cell proliferation in DR-treated rats up to rates measured in AL-treated rats. Splenocytes from DR-treated rats, relative to AL-treated rats, were more sensitive to mitogen stimulation, displayed increased cell surface expression of receptors for class 1 and 2 major histocompatibility complex molecules, and were more cytotoxic to target tumor cells. Infusion of either GH or IGF-1 in DR-treated rats further enhanced mitogen responsiveness and natural cytotoxicity but reversed the DR-induced increase in major histocompatibility complex receptors. We conclude that DR modulates MNCL progression in Fischer 344 rats through both its influence on MNCL cell proliferation via suppression of the GH:IGF-1 axis and its enhancement of host defenses against tumor cells.
利用白血病细胞移植模型以及原位和体外生物测定法，评估内源性因子在介导饮食限制（DR）诱导的Fischer 344大鼠单核细胞白血病（MNCL）抑制中的作用。接受DR处理的雄性大鼠（n = 35），喂食自由摄食（AL）量75%的NIH - 07开放式配方饮食，接种MNCL细胞12周后，其移植MNCL的发生率较低（54%对77%；P = 0.039），潜伏期更长（P = 0.015），严重程度降低（P = 0.01），优于接受AL处理的大鼠。植入接受DR处理大鼠体内的扩散小室中培养的MNCL（CRNK - 16）细胞的五日增殖率比接受AL处理的大鼠低22%（P = 0.03），表明依赖DR的可扩散因子调节原位MNCL细胞生长。与接受AL处理大鼠的血清相比，接受DR处理大鼠的血清支持更低的体外CRNK - 16细胞增殖率。与接受AL处理的大鼠相比，接受DR处理的大鼠血清中生长激素（GH）和胰岛素样生长因子1（IGF - 1）水平均降低超过50%。对一组纯化因子的体外细胞增殖活性评估表明，GH和IGF - 1而非其他15种生长因子刺激CRNK - 16细胞中的胸苷掺入。通过渗透微型泵输注GH或IGF - 1可使接受DR处理大鼠的原位和体外CRNK - 16细胞增殖恢复至接受AL处理大鼠所测水平。与接受AL处理的大鼠相比，接受DR处理大鼠的脾细胞对丝裂原刺激更敏感，1类和2类主要组织相容性复合体分子受体的细胞表面表达增加，对靶肿瘤细胞的细胞毒性更强。在接受DR处理的大鼠中输注GH或IGF - 1进一步增强了丝裂原反应性和自然细胞毒性，但逆转了DR诱导的主要组织相容性复合体受体增加。我们得出结论，DR通过抑制GH:IGF - 1轴影响MNCL细胞增殖以及增强宿主对肿瘤细胞的防御来调节Fischer 344大鼠的MNCL进展。
