Growth inhibition of squamous cell carcinoma xenografts with the polyamine analogue BE 4444
R. M. Auchter, M. A. Pickart, G. A. Nash, R. P. Qu and P. M. Harari
Department of Human Oncology, University of Wisconsin, Madison, USA.
BACKGROUND: The capacity of radiation to cure advanced head and neck
squamous cell carcinoma is compromised by the proliferation of surviving
tumor cells during the course of therapy (overall duration, often 7-9
weeks). Antiproliferative agents that inhibit tumor proliferation, even in
the absence of direct cytotoxicity, may be useful adjuncts for concurrent
use with radiation. Modulation of endogenous polyamine (PA) metabolism has
the potential to inhibit cell growth. The PA analogue
1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE 4444) is a synthetic
compound that demonstrates antiproliferative effects in human tumor cells.
OBJECTIVE: To evaluate the PA analogue BE 4444 for its inhibitory effect on
the growth of human squamous cell carcinoma xenografts in nude mice.
DESIGN: Xenografts of human squamous cell carcinomas were grown in nude
mice; then, BE 4444 was injected intraperitoneally (5 mg/kg) on a
twice-daily schedule for 8 days. Tumor growth measurements were performed
twice weekly for 8 weeks and compared with those of control mice that were
injected with sterile saline solution on the same schedule. The PA levels
in the tumor and normal tissue samples were assayed at the completion of
treatment. RESULTS: Tumor volume in the BE 4444-treated mice was reduced by
62% compared with tumor volumes in control mice, and the tumor growth rate
was reduced by 64%. This growth inhibition was maintained through
completion of the experiment. Levels of endogenous PAs were not
significantly different from control levels, suggesting that the mechanism
of action for BE 4444 is not simply PA biosynthesis inhibition.
CONCLUSIONS: The PA analogue BE 4444 is an inhibitor of human squamous cell
cancer growth. Further studies are in progress to characterize the
potential value of PA analogues as adjuncts to radiation therapy for
rapidly proliferating squamous cell carcinoma of the head and neck.