COMPARATIVE ACTIVITY OF N-(4-HYDROXYPHENYL)-ALL-TRANS-RETINAMIDE AND ALPHA-DIFLUOROMETHYLORNITHINE AS INHIBITORS OF LYMPHOMA INDUCTION IN PIM TRANSGENIC MICE

The activities of the retinoid, N-(4-hydroxyphenyl)-all-trans-retinami de (4-HPR) and the polyamine synthesis inhibitor, alpha-difluoromethyl ornithine (DFMO), as inhibitors of lymphoma induction in PIM transgeni c mice were evaluated, Lymphoma was induced in male PIM mice by a sing le intraperitoneal injection of 50 mg N-ethyl-N-nitrosourea (ENU) per kg body weight, Continuous dietary administration of 4-HPR (391, 196 o r 98 mg/kg diet) or DFMO (1000, 500 or 250 mg/kg diet) was initiated i mmediately after ENU administration, and was continued until the end o f the study at 35 weeks, At 20 weeks: post-ENU, the high dose of 4-HPR reduced both lymphoma incidence and associated mortality, However, th e protection conferred by 4-HPR represented a delay rather than an inh ibition of neoplastic development, since both lymphoma incidence and m ortality at study termination were similar in dietary controls and all groups treated with 4-HPR. DFMO had no effect on lymphoma incidence, latency or mortality at any point in the study, These results suggest that 4-HPR or other retinoids may be effective in the prevention of ly mphoma induction, whereas inhibition of polyamine biosynthesis does no t appear to present a useful mechanistic target for the chemopreventio n of lymphoid neoplasia, The PIM transgenic mouse provides a useful in vivo model for the rapid evaluation of chemopreventive agents.