A novel polyamine analog (SL-11093) inhibits growth of human prostate tumor xenografts in nude mice.
OBJECTIVE
We tested the polyamine analog SL-11093 (3,8,13,18-tetraaza-10,11-[(E)-1,2-cyclopropyl]eicosane tetrahydrochloride) as an effective chemotherapeutic agent against human prostate cancer grown in nude mice.


METHODS
NCr-nu mice grafted with DU-145 human prostate tumor cells were treated i.p. with SL-11093 at 50 mg/kg q1dx5 for either three or five cycles separated by intervals of about 10-15 days.


RESULTS
In treated animals, tumor growth remained arrested for up to 100 days with minimal animal weight loss. None of the animals died during the treatment and in one experiment two out of six animals showed no palpable tumor. SL-11093 was readily taken up by the tumors, where its levels remained elevated for about 48 h after the end of drug administration. In liver and in kidney, SL-11093 (a (alpha)N,(omega)N-bisethyl derivative) was oxidatively N-deethylated predominantly to its monoethyl and di-deethyl derivatives. In time, the monoethyl derivative was further dealkylated, with a loss of an aminobutyl chain to form an aminomethyl cyclopropyl derivative. In tumor (and in lung), N-dealkylation reactions were less evident.


CONCLUSIONS
SL-11093 is an effective chemotherapeutic agent against a human prostate tumor xenograft grown in nude mice. The drug accumulation and slow metabolism in tumor compared to other tissues would most likely reduce systemic toxicity of the drug and contribute to a larger therapeutic window for SL-11093 as compared to other cytotoxic polyamine analogs.
Frydman
Benjamin
B
SLIL Biomedical Corporation, Suite C, 535 Science Dr, Madison, WI 53711-1066, USA.
Porter
Carl W
CW
Maxuitenko
Yulia
Y
Sarkar
Aparajita
A
Bhattacharya
Subhra
S
Valasinas
Aldonia
A
Reddy
Venodhar K
VK
Kisiel
Nick
N
Marton
Laurence J
LJ
Basu
Hirak S
HS
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D009955:Ornithine Decarboxylase; D011073:Polyamines; D012436:S-Adenosylmethionine; D000099228:Diamine N-Acetyltransferase; C475839:3,8,13,18-tetraaza-10,11-((E)-1,2-cyclopropyl)eicosane tetrahydrochloride