In vivo effects of 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A) and alpha-difluoromethylornithine (DFMO) on L1210 growth, cell-cycle phase distribution and polyamine contents.
We studied the in vivo effects of 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A), alpha-difluoromethylornithine (DFMO) and a combination of CGP 48664A-DFMO on tumor growth, cell-cycle phase distribution and polyamine contents. DBA-2 mice were inoculated i.p. with 10(5) L1210 cells on day 0, treated i.p. on days 1-4 and killed on day 5. As compared to controls, CGP 48664A, DFMO and the CGP 48664A-DFMO combination reduced L1210 cell numbers by 33, 43 and 85%, respectively. CGP 48664A did not affect cell-cycle phase distribution. DFMO and the CGP 48664A-DFMO combination caused a moderate and a heavy accumulation in G0/G1- and G2/M-phases, respectively. Compared with controls, the CGP 48664A-DFMO combination reduced putrescine, spermidine and total polyamines, but did not affect spermine. Compared with CGP 48664A, the CGP 48664A-DFMO combination caused lower putrescine and total polyamines, higher spermine, but no change in spermidine. Compared with DFMO, the CGP 48664A-DFMO combination caused higher putrescine and spermidine, lower spermine, but no change in total polyamine levels. We conclude that CGP 48664A potentiates the cystostatic effect of DFMO in vivo. The resulting growth inhibition is accompanied by an accumulation in G0/G1- and G2/M-phases and a reduction of putrescine and spermidine. The data suggest that perturbed polyamine composition rather than reduced spermidine or total polyamine pool size causes a profound growth inhibition.
Dorhout
B
B
Central Laboratory for Clinical Chemistry, University Hospital Groningen, The Netherlands.
te Velde
R J
RJ
Ferwerda
H
H
Kingma
A W
AW
de Hoog
E
E
Muskiet
F A
FA
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015317:Biogenic Polyamines / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D000518:Eflornithine / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA
D000578:Amidines; D000970:Antineoplastic Agents; D015317:Biogenic Polyamines; D004791:Enzyme Inhibitors; D007189:Indans; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D012437:Adenosylmethionine Decarboxylase; D000518:Eflornithine