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Inhibition of Moloney Murine Lymphoma and Sarcoma Growth in Vivo by Dietary Retinoids¹

Birmingham Veterans Administration Medical Center and the Department of Comparative Medicine [D. L. D., E. W. L.], Microbiology [E. W. L.], and Surgery [E. W. L.], University of Alabama at Birmingham, University Station, Birmingham, Alabama 35294; and Medicinal Chemistry Division [Y. F. S.], Southern Research Institute, Birmingham, Alabama 35255-5305

The effects of dietary retinoids on the growth of Moloney lymphoma (LSTRA) and sarcoma (MSC) in BALB/c mice were evaluated. Transplantable syngeneic Moloney lymphoma and sarcoma tumors are immunogenic. Preimmunization with LSTRA cells provides protection against subsequent challenge and sarcomas spontaneously regress following injection of an appropriate inoculum of MSC cells. In normal mice fed varying concentrations of all-trans-retinoic acid (RA) and given injections of 10³ LSTRA cells, RA caused a dose-dependent increase in the number of survivors; 50% of the mice fed RA at 50 mg/kg of diet were long-term survivors. All animals died that were fed a control diet and challenged with 10³ LSTRA cells. Athymic (nu/nu) mice fed RA were not protected against lymphoma growth, whereas euthymic (nu/+) mice were; therefore, the antitumor effect of RA was thymus dependent. Primary immunization with irradiated LSTRA in the presence of RA caused a significant increase in cell-mediated cytotoxicity by spleen cells at 4 days after immunization. However, challenge of animals preimmunized with LSTRA in the presence of dietary RA revealed a dose-dependent inhibition of memory. A significant reduction in MSC growth was also observed in normal mice fed 13-cis-retinoic acid (cRA). A comparison of the primary antilymphoma effect of dietary RA, cRA, N-(all-trans-retinoyl)-DL-leucine (RL), and N-(4-hydroxyphenyl)retinamide (4-HPR) revealed an efficacy hierarchy of RL > RA > cRA > 4-HPR with RL producing 70% long-term survivors at 115 days after challenge with 10³ LSTRA cells. These studies indicate that retinoids can inhibit the growth of transplantable, retroviral-induced, immunogenic tumors by thymus-dependent mechanisms and that a newly synthesized retinoylamino acid (RL) is more potent than RA at inhibiting Moloney lymphoma growth.

¹ This work was supported by VA Medical Research, Grants 2T32RR07003-11 and RO1-CA-38008 from the National Institutes of Health, and Contract NO1-CA-26009 and Grant 1PO1-CA-34968 from Division of Cancer Etiology, National Cancer Institute.

² To whom requests for reprints should be sent, at Emory University School of Medicine, Woodruff Memorial Research Building, 1639 Pierce Drive, P.O. Drawer TT, Atlanta, GA 30322.

Received 5/24/88. Revised 9/15/88. Accepted 9/27/88.