Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

M. A. Desiderio, D. Bergamaschi, E. Mascellani, P. De Feudis, E. Erba, M. D'Incalci

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14 Citations (Scopus)

Abstract

Inhibitors of ornithine decarboxylase (ODC), such as α-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)-β-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 cyde 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.

Original languageEnglish
Pages (from-to)1028-1034
Number of pages7
JournalBritish Journal of Cancer
Volume75
Issue number7
Publication statusPublished - 1997

Fingerprint

Topoisomerase II Inhibitors
Spermine
Alkylating Agents
Polyamines
Carmustine
Putrescine
Spermidine
CC 1065
Adenosylmethionine Decarboxylase
Pharmaceutical Preparations
Eflornithine
Type II DNA Topoisomerase
Melphalan
DNA
G1 Phase
Etoposide
Phenylalanine
Ovarian Neoplasms
Doxorubicin
Cisplatin

Keywords

  • AbeAdo
  • Anti-cancer agents
  • Inhibitor of SAMDC
  • MAP
  • Novel inhibitor of ornithine decarboxylase
  • Polyamines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{3a3efdfaeec14121b4743881f0e391b5,
title = "Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors",
abstract = "Inhibitors of ornithine decarboxylase (ODC), such as α-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)-β-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 cyde 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.",
keywords = "AbeAdo, Anti-cancer agents, Inhibitor of SAMDC, MAP, Novel inhibitor of ornithine decarboxylase, Polyamines",
author = "Desiderio, {M. A.} and D. Bergamaschi and E. Mascellani and {De Feudis}, P. and E. Erba and M. D'Incalci",
year = "1997",
language = "English",
volume = "75",
pages = "1028--1034",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "7",

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TY - JOUR

T1 - Treatment with inhibitors of polyamine biosynthesis, which selectively lower intracellular spermine, does not affect the activity of alkylating agents but antagonizes the cytotoxicity of DNA topoisomerase II inhibitors

AU - Desiderio, M. A.

AU - Bergamaschi, D.

AU - Mascellani, E.

AU - De Feudis, P.

AU - Erba, E.

AU - D'Incalci, M.

PY - 1997

Y1 - 1997

N2 - Inhibitors of ornithine decarboxylase (ODC), such as α-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)-β-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 cyde 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.

AB - Inhibitors of ornithine decarboxylase (ODC), such as α-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)-β-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 cyde 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.

KW - AbeAdo

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KW - Inhibitor of SAMDC

KW - MAP

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JO - British Journal of Cancer

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