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-retinamide (4-HPR) and the polyamine synthesis inhibitor, alpha-difluoromethylornithine (DFMO), as inhibitors of lymphoma induction in PIM transgenic mice were evaluated. Lymphoma was induced in male PIM mice by a single intraperitoneal injection of 50 mg N-ethyl-N-nitrosourea (ENU) per kg body weight. Continuous dietary administration of 4-HPR (391, 196 or 98 mg/kg diet) or DFMO (1000, 500 or 250 mg/kg diet) was initiated immediately after ENU administration, and was continued until the end of the study at 35 weeks. At 20 weeks post-ENU, the high dose of 4-HPR reduced both lymphoma incidence and associated mortality. However, the protection conferred by 4-HPR represented a delay rather than an inhibition of neoplastic development, since both lymphoma incidence and mortality 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 lymphoma induction, whereas inhibition of polyamine biosynthesis does not appear to present a useful mechanistic target for the chemoprevention of lymphoid neoplasia. The PIM transgenic mouse provides a useful in vivo model for the rapid evaluation of chemopreventive agents.
McCormick
D L
DL
Life Sciences Department, IIT Research Institute, Chicago, IL 60616, USA.
Johnson
W D
WD
Rao
K V
KV
Bowman-Gram
T
T
Steele
V E
VE
Lubet
R A
RA
Kelloff
G J
GJ
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000518:Eflornithine / Q000627:therapeutic use*; D017313:Fenretinide / Q000627:therapeutic use*; D008223:Lymphoma / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic
D016588:Anticarcinogenic Agents; D017313:Fenretinide; D000518:Eflornithine