The cardioprotective and DNA topoisomerase II inhibitory agent dexrazoxane (ICRF-187) antagonizes camptothecin-mediated growth inhibition of Chinese hamster ovary cells by inhibition of DNA synthesis.
Anticancer Drugs
; 10(1): 47-54, 1999 Jan.
Article
em En
| MEDLINE
| ID: mdl-10194547
ABSTRACT
Dexrazoxane (ICRF-187), which is clinically used to reduce doxorubicin-induced cardiotoxicity, has cell growth inhibitory properties through its ability to inhibit the catalytic activity of DNA topoisomerase II. A study was undertaken to investigate whether preincubating Chinese hamster ovary cells (CHO) with dexrazoxane prior to camptothecin treatment resulted in potentiation. Camptothecin is a DNA topoisomerase I poison. It was found that pretreating CHO cells with concentrations of dexrazoxane sufficient to strongly inhibit topoisomerase II for periods from 18 to 96 h resulted in significant antagonism of camptothecin-mediated growth inhibition. Lower concentrations that were sufficient to cause partial inhibition of topoisomerase II and partial dexrazoxane-mediated cell growth inhibition had little effect on camptothecin-mediated growth inhibition. Neither topoisomerase I protein levels nor camptothecin-induced topoisomerase I-DNA covalent complexes were affected by dexrazoxane concentrations that were sufficient to cause antagonism of camptothecin-induced growth inhibition. However, under these experimental conditions, dexrazoxane caused a decrease in DNA synthesis. Therefore, results presented here confirm the importance of the DNA synthesis-dependent replication fork interaction with topoisomerase I-DNA covalent complexes for the expression of camptothecin activity. It is concluded that dexrazoxane and camptothecin analogs should be used with caution in combination chemotherapy.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Razoxano
/
Camptotecina
/
Fármacos Cardiovasculares
/
Células CHO
/
Inibidores da Topoisomerase II
Limite:
Animals
Idioma:
En
Revista:
Anticancer Drugs
Assunto da revista:
ANTINEOPLASICOS
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Canadá