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Antitumor Activity of N,N'-Bis(ethyl)spermine Homologues against Human MALME-3 Melanoma Xenografts¹

Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263 [C. W. P., R. J. B.], and Department of Medicinal Chemistry, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610 [R. J. B.]

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 >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.

¹ This work has been supported in part by grants CA-51524, CA-22153, CA-37606, CA-13038, and CA-16056 from the National Cancer Institute, and by a grant from the Buffalo Foundation, Buffalo, NY.

² To whom requests for reprints should be addressed.

Received 9/20/91. Accepted 2/24/92.

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