Growth inhibition of two solid tumors in mice, caused by polyamine depletion, is not attended by alterations in cell-cycle phase distribution.
We studied the effect of polyamine depletion on growth and cell cycle characteristics of subcutaneously grown Lewis lung carcinoma (LLC) and fibrosarcoma (FIO 26) in mice. Polyamine depletion was achieved by inhibition of ornithine decarboxylase using 2-(difluoromethyl)ornithine, limitation of exogenous polyamines by administration of a polyamine-poor diet and decontamination of the gastrointestinal tract, and inhibition of endogenous polyamine reutilization by N,N'-bis-(2,3-butadienyl)putrescine (MDL 72527). Determination of S-phase cells was performed in tumor-cell suspensions by flow cytometry and in tumor tissue sections by microscopy, following in vivo labelling with 5-bromo-2'-deoxyuridine (BUdR). DNA synthesis rate was estimated from the incorporation of in vivo-injected [3H]-thymidine (3H-TdR). Both solid tumors almost completely stopped growing after access to polyamines was blocked. Growth inhibition was, however, not attended by changes in cell-cycle-phase distribution. Paradoxically, we measured increased in vivo 3H-TdR incorporation rates and unaltered BUdR-linked staining intensity in treated tumors. Injection of putrescine into treated LLC-bearing mice resulted in an increase in intracellular putrescine and spermidine concentrations, a slight increase in the number of S-phase cells and a marked drop in DNA synthesis rate within the following 9 hr.
Hessels
J
J
Central Laboratory for Clinical Chemistry, University Hospital Groningen, The Netherlands.
Kingma
A W
AW
Muskiet
F A
FA
Sarhan
S
S
Seiler
N
N
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D000518:Eflornithine / Q000494:pharmacology; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology*; D007700:Kinetics; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000031:analogs & derivatives / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000473:pathology*
D011073:Polyamines; C044445:MDL 72527; D011700:Putrescine; D000518:Eflornithine