In vivo manipulation of L1210 cell cycle phase distribution with alpha-difluoromethylornithine, 4-amidinoindan-1-one 2'-amidinohydrazone and N1-acetylspermine.
We investigated whether the in vivo growth inhibitory effect of the combination of 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664A) and alpha-difluoromethylornithine (DFMO) is reversible by treatment with N1-acetylspermine (N1-acSp). DBA-2 mice were inoculated with 10(5) L1210 cell i.p. on day 0. From day 1 they received 2.50 mg CGP 48664A/kg i.p. once daily and 500 mg DFMO/kg i.p. twice daily. On day 5 they received 3 x 2500 nmol N1-acSp i.p. with 15-min intervals. L1210 cell numbers, S-phase percentage and polyamine contents, and liver and spleen polyamine contents were monitored in the following 48 h. Four days treatment with CGP 48664A/DFMO reduced L1210 cell numbers, S-phase, and spermidine. N1-acSp treatment increased L1210 spermidine from < or = 8 h and percentage S-phase from 12 h. Maxima for spermidine and S-phase were reached at < or = 8 and 18 h, respectively. These were below levels of untreated controls. Decreases were noted from 12 and 18 h, respectively. N1-acSp was detectable in L1210 from 0-18 h. Liver spermidine was decreased by CGP 48664A/DFMO. After N1-acSp treatment, liver N1-acSp and N1-acSd increased from < or = 8 h, reached maxima at < or = 8 and 10 h, respectively, and were undetectable from 15 h. We conclude that the in vivo growth inhibitory effect of CGP 48664A/DFMO is reversible by N1-acSp treatment. The liver is probably involved in N1-acSp terminal catabolism. The effect of the polyamine depletion-repletion scheme on S-phase cell numbers may be much more profound than present estimates from 5-bromo-2'-deoxyuridine incorporation.
Dorhout
B
B
Central Laboratory for Clinical Chemistry, University Hospital Groningen, Netherlands.
Ferwerda
H
H
Kingma
A W
AW
de Hoog
E
E
Muskiet
F A
FA
D000578:Amidines / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002452:Cell Count; D000518:Eflornithine / Q000008:administration & dosage*; D005260:Female; D007189:Indans / Q000008:administration & dosage*; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D016196:S Phase / Q000187:drug effects; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000578:Amidines; D007189:Indans; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; C029452:N'-acetylspermine; D013096:Spermine; D000518:Eflornithine