The
spermine analogues, N1,N12-bis(ethyl)spermine (
BESPM),
N1,N11-bis(ethyl)norspermine (
BENSPM), and N1,N14-bis(ethyl)-homospermine (
BEHSPM) behave similarly in down-regulating the key
polyamine biosynthetic
enzymes,
ornithine and
S-adenosylmethionine decarboxylase, but differ distinctly in their abilities to induce the
polyamine catabolic
enzyme,
spermidine/
spermine-N1-
acetyltransferase;
BENSPM is 6-fold more effective than
BESPM in increasing
spermidine/
spermine-N1-
acetyltransferase activity and
BEHSPM is 10-fold less effective. Since MALME-3 human
melanoma cells are extremely responsive to
spermidine/
spermine-N1-
acetyltransferase induction (i.e., increases greater than 200-fold) and since this induction correlates with growth inhibition among
melanoma cell lines, the ability of these homologues to inhibit the growth of MALME-3 xenografts was examined. Analogues were administered i.p. three times per day (i.e., every 8 h) for 6 days at the following doses per injection:
BEHSPM, 1.5, 3, or 6 mg/kg;
BESPM, 10, 20, or 40 mg/kg;
BENSPM, 20, 40, or 80 mg/kg. At the highest tolerated doses, all of the analogues fully suppressed growth of established (100-200 mm3) MALME-3
tumor during treatment and sustained
tumor growth inhibition following treatment as follows:
BEHSPM, 14 days;
BESPM, 27 days, and
BENSPM, 37 days. The
tumor delay (to reach 1000 mm3 relative to control) at the highest tolerated doses was as follows:
BEHSPM, 20 days;
BESPM, 34 days, and
BENSPM, 63 days. The rank order of analogue host toxicity as indicated by
weight loss was opposite that for antitumor activity,
BEHSPM was most toxic,
BESPM, intermediate, and
BENSPM, least toxic. Thus, the most effective of the three homologues,
BENSPM, was best tolerated, and produced an initial
tumor regression, full suppression of
tumor regrowth during treatment, and sustained inhibition of
tumor regrowth for 37 days
after treatment stopped. Owing to its potent antitumor activity, mild host toxicity, and novel apparent mechanism of action,
BENSPM is being considered for further development toward clinical trial.