Inhibitors of
ornithine decarboxylase (ODC), such as
alpha-difluoromethylornithine (DFMO), may influence the cytotoxicity of anti-tumour agents that interact with
DNA. Intracellular levels of
putrescine and
spermidine were markedly reduced by ODC inhibitors while the level of
spermine, which is the main
polyamine in nuclei, was unchanged. By combining a novel inhibitor of ODC, such as (2R, 5R)-6-heptyne-2,5-diamine (MDL 72.175, MAP), with an inhibitor of
S-adenosylmethionine decarboxylase (SAMDC), such as 5'-[[(Z)-4-aminobut-2-enyl]methylamino]-5'-
deoxyadenosine (MDL 73.811,
AbeAdo),
spermine was selectively depleted in a human
ovarian cancer cell line OVCAR-3 (i.e.
spermine became almost undetectable whereas the levels of
spermidine and
putrescine were not affected). The depletion of
spermine blocked
DNA synthesis with a consequent accumulation of cells in the G1 phase of the cell cycle. Pretreatment with MAP plus
AbeAdo did not change the cytotoxicity of
alkylating agents, such as
L-phenylalanine mustard (
L-PAM), 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo-[2.2.1]
heptane diperchlorate (DABIS),
1,3-bis(2-chloroethyl)-1-nitrosourea (
BCNU),
cis-diamminedichloroplatinum (II) (cis-DDP), N-deformyl-N-[4-N-N,N-bis (2-chloroethylamino)benzoyl] (
tallimustine) or
CC-1065, whereas it markedly reduced the cytotoxicity of
DNA topoisomerase II inhibitors, such as
doxorubicin (DX) and 4'-demethylepipodophyllotoxin-5-(4,6-O)-ethylidene- beta-D-glycopyranoside (VP-16). The addition of
spermine before
drug treatment restored the sensitivity to the
DNA topoisomerase II inhibitors, thus indicating that the reduced effect was related to the intracellular
spermine level. The reason for the reduction in cytotoxicity is unclear, but it does not appear to be related to a cell cycle effect or to a decrease in the intracellular level of
DNA topoisomerase II. Drugs that modify
polyamine biosynthesis are under early clinical development as potential new anti-tumour agents. These findings illustrate the need for caution in combining such drugs with
DNA topoisomerase II inhibitors.