Treatment of nude mice with 4-amidinoindan -1- one2 '- amidinohydrazone, a new S-adenosylmethionine decarboxylase inhibitor, delays growth and inhibits metastasis of human melanoma cells.
CGP 48664A (4-amidinoindan-1-one2'-amidinohydrazone) is a novel inhibitor of S-adenosyl-methionine decarboxylase (SAMDC), a key enzyme in the biosynthesis of polyamines, which are themselves essential for proliferation of mammalian cells. Seven different human melanoma cell lines were treated in vitro with CGP 48664A. High, intermediate and low levels of cytostasis were induced in four, one and two melanoma lines, respectively. This cytostasis was reversed by the addition of exogenous spermidine or spermine to the culture medium. The heterogeneous low metastatic (CGP 48664A-resistant) A375P cells and highly metastatic (CGP 48664A-sensitive) A375SM cells were implanted into the subcutis or injected intravenously into nude mice. Systemic daily administration of CGP 48664A significantly reduced the size of cutaneous lesions and the number of lung metastases in mice implanted with A375SM cells. No beneficial effects were found in mice injected with A375P cells. Drug activity was dose dependent, and maximal effects were observed when treatment began in mice with small tumour burdens. The data suggest that CGP 48664A is effective against melanoma metastasis in nude mice and that its activity should be tested in combination with other cytoreductive agents.
Gutman
M
M
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Beltran
P J
PJ
Fan
D
D
Delworth
M G
MG
Singh
R K
RK
Wilson
M R
MR
Fidler
I J
IJ
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013095:Spermidine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000578:Amidines; D003470:Culture Media; D007189:Indans; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D013096:Spermine; D012437:Adenosylmethionine Decarboxylase; D013095:Spermidine