Timed daily administration of prolactin and corticosteroid hormone reducesmurine tumor growth and enhances immune reactivity

In the present study, we investigated the time-dependent interactive effect s of daily injections of prolactin (PRL) and corticosterone (CORT) on the a ctivation of lymphocyte function and inhibition of tumor growth in vivo in mice. BALB/c mice were injected subcutaneously with EMT-6 fibrosarcoma cell s (a murine connective tissue tumor cell derived from mammary gland), and t hen different groups of animals were treated with PRC (1 mu g/g body weight [BW] ip) at Oh, 4h, 8h, 12h, 16h, or 20h after CRT (1 mu g/g BW ip) daily for 10 days. Different control groups were vehicle treated or treated with either hormone alone. Mice were kept in constant light 1 week before and du ring injections and in a 14:10 Light-dark cycle thereafter. Tumor progressi on was monitored for up to 21 days after the cessation of treatment, and th ereafter spleen lymphocytes were harvested and tested for mitogen-triggered proliferation. Prolactin administration at 8h or 16-20h after corticostero id treatment reduced tumor volume by 77% and 49%, respectively, relative to vehicle-treated controls. Other time relations of hormone treatment were i neffectual. Further studies indicated that the immunosuppressant cyclospori n A (CSA) substantially stimulated tumor growth; this effect was completely abrogated by a simultaneous 8h related hormone treatment. However, the 8h hormone treatment was ineffective in inhibiting tumor growth in T-cell-defi cient nude mice. Spleen lymphocytes from tumor-bearing (TB) mice showed an elevated basal proliferative capacity stimulated by concanavalin A (ConA; a stimulus for T-cell proliferation) and lipopolysaccharide (LPS; a stimulus for B-cell proliferation) compared to non-TB mice. Spleen lymphocytes from TB mice treated with CORT and PRL at 8h intervals exhibited an increased s pontaneous (as well as LPS- and ConA- triggered) proliferation (by 104%, 48 %, and 70%, respectively) compared with vehicle control TB mice. Fluorescen ce-activated cell sorting (FACS) analysis of splenocytes from hormone-treat ed animals indicated a 34-100% increase in the CD4(+) (e.g., T helper cell) population. Treatment of animals with either hormone alone did not inhibit tumor growth or stimulate immune function relative to vehicle controls. Th e daily rhythms of plasma PRL, CORT, and thyroxine were all substantially a ltered by the presence of tumor in these mice. These results indicate that appropriately timed daily treatment of PRL and CORT can attenuate tumor gro wth, in part, via activation of antitumor immune mechanisms. Collectively, these data suggest that circadian neuroendocrine activities must be tempora lly organized appropriately to inhibit tumor growth.