Cyclopropane-Containing Polyamine Analogues Are Efficient Growth Inhibitors of a Human Prostate Tumor Xenograft in Nude Mice

Abstract

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.

Macrocyclic Polyamines Deplete Cellular ATP Levels and Inhibit Cell Growth in Human Prostate Cancer Cells

“…The DuPro cell line was selected for further studies, since it was known to be a more sensitive cell line than PC-3 to treatment with polyamines. 18 Inhibition of growth of DuPro cells was assessed after treatment with the macrocycles for 3, 4, and 5 days ( Figure 2). All five macrocyclic polyamines showed significant growth inhibitory effects within the concentration range of 5-10 µM.…”

“…The basic structure of the budmunchamines is the [17]-N 4 tetraaza macrocycle 1; its synthesis has been reported elsewhere. 13 Macrocycle 20 and macrocycle 13 are the [16]-N 4 and the [18]-N 4 analogues of 1.…”

Thermodynamics of the DNA binding of biogenic polyamines: Calorimetric and spectroscopic investigations

“…In some tumour cells higher concentration of polyamines, compared to normal cells, is present and this has fuelled speculation that regulation of polyamine concentration may be a potential mechanism for cancer chemotherapy [2,3,[12][13][14][15][16]. The effectiveness of polyamine analogues, as anti-proliferative agents against many tumour cell lines provide evidence for nucleic acid interaction of polyamines [17][18][19][20][21][22]. Structurally, polyamines have cationic groups (figure 1) with multiple positive charges (four for spermine, three for spermidine, two each for putrescine and cadaverine) that enable them to interact with anionic nucleic acids protecting the latter from damaging agents [23][24][25][26].…”

Gambogic Acid Inhibits Proliferation of Human Lung Carcinoma SPC-A1 Cells in Vivo and in Vitro and Represses Telomerase Activity and Telomerase Reverse Transcriptase mRNA Expression in the Cells

“…The Telomerase PCRenzyme-linked immunosorbent assay (ELISA) kit, TriPure Isolation Reagent, and DNase-free RNase were purchased from Roche. 13) Transplantable tumors (induced by 5ϫ10 6 SPC-A1 cells injected s.c. into nude mice) were chopped into fragments (about 1.5 mm 3 ), each of which was transplanted (s.c.) into the right axillary fossa of 24 nude mice. When a tumor had increased to 100-300 mm 3 , the mice were equally randomized into 4 groups (negative control, 3 mg/kg OPT, 4 and 8 mg/kg GA).…”