THE GROWTH-HORMONE - INSULIN-LIKE GROWTH FACTOR-I AXIS IS A MEDIATOR OF DIET RESTRICTION-INDUCED INHIBITION OF MONONUCLEAR CELL LEUKEMIA INFISCHER RATS

A leukemia cell transplant model and both in situ and in vitro bioassa ys were used to assess the roles of endogenous factors in mediating di et restriction (DR)-induced inhibition of mononuclear cell leukemia (M NCL) in Fischer 344 rats. DR-treated male rats (n = 35), which were fe d 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 l atency (P = 0.015) and decreased severity (P = 0.01) than AL-treated r ats 12 weeks after inoculation with MNCL cells. Five-day proliferation rates of cultured MNCL (CR.NK-16) cells in diffusion chambers implant ed 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 M NCL cell growth. Serum from DR-treated rats supported lower in vitro C RNK-16 cell proliferation rates relative to serum from AL-treated rats . Serum levels of both growth hormone (GH) and insulin-like growth fac tor 1 (IGF-1) were over 50% lower in DR-versus AL-treated rats. An eva luation of the in vitro cell proliferative activity of a panel of puri fied factors showed that GH and IGF-1, but not 15 other growth factors , stimulated thymidine incorporation in CRNK-16 cells. Infusion of eit her GH or IGF-1 via osmotic minipumps restored in situ and in vitro CR NK-16 cell proliferation in DR-treated rats up to rates measured in AL -treated rats. Splenocytes from DR-treated rats, relative to AL-treate d rats, were more sensitive to mitogen stimulation, displayed increase d cell surface expression of receptors for class 1 and 2 major histoco mpatibility complex molecules, and were more cytotoxic to target tumor cells. Infusion of either GH or IGF-1 in DR-treated rats further enha nced 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 throug h both its influence on MNCL cell proliferation via suppression of the GH:IGF-1 axis and its enhancement of host defenses against tumor cell s.