Certain N-alkylated analogues of the natural
polyamine spermine have been found to disrupt
polyamine pool homeostasis and inhibit
tumor cell growth. The most effective of these analogues, N1, N11-diethylnorspermine (
DENSPM), apparently depletes intracellular
polyamine pools primarily by inducing the
polyamine acetylating
enzyme spermidine/
spermine N1-acetyltransferase, which contributes to
polyamine depletion via increased
polyamine excretion and catabolism. In this report, the experimental therapeutic efficacy of
DENSPM was further examined with the use of other human solid
tumor xenografts, including A121 ovarian
carcinoma, A549
lung adenocarcinoma, HT29 colon
carcinoma, and SH-1
melanoma, and compared with previously obtained findings with MALME-3M and PANUT-3 human
melanomas. In vitro studies indicated that the growth sensitivity of most tumor cell lines to
DENSPM was similar, with characteristically flat dose-response curves and IC50s ranging between 0.1 and 1 micrometer the only exception was the HT29 colon
carcinoma cell line, which had an IC50 of >100 micrometer. For in vivo studies,
DENSPM was administered by i.p. injection to female nude athymic mice at 40 and/or 80 mg/kg 3 times a day (every 8 h) for 6 days or by continuous s.c. infusion with the use of Alzet pumps at 120, 240, or 360 mg/kg/day for 4 days. Treatment began after s.c.
tumor xenografts had reached 100-200 mm3. The SH-1
melanoma, A549
lung adenocarcinoma, and A121 ovarian
carcinoma xenografts responded well to the i.p. administration of analogue with obvious
tumor regressions, long-term
tumor growth suppressions, and a significant proportion (up to 40%) of apparent cures (i.e., lack of
tumor regrowth). However, in similarity to in vitro findings, HT29 colon
carcinoma xenografts responded poorly to
DENSPM treatment. Massive induction of N1-acetyltransferase activity and extensive depletion of
polyamine pools were consistent findings in most
tumor types after in vivo or in vitro treatment with
DENSPM. The rapidly growing human LOX
melanoma xenograft, however, demonstrated poor induction of N1-acetyltransferase activity and the poorest response to
DENSPM treatment. In nude athymic mice with MALME-3M
melanoma xenografts, constant infusion delivery of
DENSPM resulted in prolonged inhibition of
tumor growth and long-term
tumor regressions comparable to those produced by multiple i.p.
injections. On the basis of the unique structure of
DENSPM, novel target and mode of intervention, mild host toxicity, and activity against different human solid
tumor xenografts,
DENSPM is currently being developed as an
antitumor agent in humans.