Polyamine analogues 7, 10, 18, 27, and 32 containing
cyclopropane rings were obtained by chemical synthesis. Their
antineoplastic activities were assessed against the cultured human prostate tumor cell lines DU-145, DuPro, and PC-3. Decamines 32 and 27 exhibited variable levels of cytotoxicity against all three cell lines, while 7, 10, and 18 were efficacious against DU-145 and DuPro. Maximum tolerated doses (MTD) for all five compounds in a NCr-nu mouse model were determined at dosing schedules of q1d x 5 (ip) in two cycles with a break of 10 days between cycles. Their antitumor efficacies were then tested against DU-145
tumor xenografts in mice treated with all five agents at their respective MTDs. In addition, the efficacies of 7 and 10 against the same
tumor xenograft were assessed at doses below their respective MTDs. In all experiments, administration began two weeks after
tumor implantation. All compounds efficiently inhibited
tumor growth for up to 50 days postimplantation, with negligible animal
body weight loss.
Tetramine 10 and
hexamine 18 were the most efficient among the five analogues in arresting
tumor growth.
Tetramine 10 containing two
cyclopropane rings had the lowest systemic toxicity as reflected in animal
body weight loss. It was further assessed at a weekly administration regimen of (q1w x 4) in two cycles with a four-week break between the cycles. At this dosing schedule, 10 again efficiently arrested
tumor growth with negligible effect on animal
body weight.
Tetramine 10 also arrested the growth of large
tumors (ca. 2000 mm(3)) treated 66 days postimplantation. Studies on the metabolism of 10 showed that it accumulates in
tumor within 6 h after the end of administration and reached a maximum level 72 h after cessation of dosing. Intracellular concentrations of 10 in liver and kidney were much smaller when compared to those in the
tumor when measured 72 h after cessation of dosing. In liver and kidney, the deethyl metabolites of 10 accumulated over a 96 h period after cessation of dosing.