Synergistic effects of ICI 182,780 on the cytotoxicity of cisplatin in cervical carcinoma cell lines

Cancer Chemother Pharmacol (2004) 53: 533540

DOI 10.1007/s00280-003-0760-3ORIGINAL ARTICLEPatricia Garca-Lopez Mauricio Rodrguez-Dorantes

Enrique Perez-Cardenas Marco CerbonAlejandro Mohar-BetancourtSynergistic effects of ICI 182,780 on the cytotoxicity of cisplatin

in cervical carcinoma cell linesReceived: 26 June 2004 / Accepted: 4 December 2003 / Published online: 29 January 2004

Springer-Verlag 2004Abstract Purpose: We investigated the ability of the

novel pure antiestrogen ICI 182,780 to modulate the

cytotoxic eects of cisplatin in several cervical cancer cell

lines. Methods: The eect of cisplatin alone and cisplatin

combined with ICI 182,780 on cellular death was studied

using an assay based on a tetrazolium dye (sodium

3-[1-(phenylamino-carbonyl)-3,4-tetrazolium], XTT).

Before and after treatment with ICI 182,780, expression

of the estrogen and progesterone receptor genes were

assessed by a reverse transcriptase polymerase chain

reaction (RT-PCR). Cell-cycle modications after combined treatment with cisplatin and ICI 182,780 were

studied by ow cytometry. Results: Analysis of the data

by the isobologram method showed that the combination of ICI 182,780 and cisplatin produced a synergistic

antiproliferative eect in cervical cancer cells. The eect

of ICI 182,780 on the cytotoxicity of cisplatin could be

mediated, at least partially, by inhibition of estrogen and

progesterone gene expression and by arresting the cell

cycle at the G2/M phase. Conclusions: Our results suggest that ICI 182,780 can improve the ecacy of

cisplatin in cancer cells and that this antihormonal drug

therapy may be a useful candidate for further evaluation

in combination with antineoplastic drugs, particularly

cisplatin, in the treatment of cancer.Keywords Cervical cancer Cisplatin Drug

synergism ICI 182,780 Cancer therapyIntroductionCisplatin and its derivatives are important drugs in

cancer therapy. It has been widely used for its potent

cytotoxic eects upon a variety of tumor types including

testicular, ovarian, and cervical carcinoma [2, 12, 26, 30].

However, the administration of cisplatin is associated

with serious side eects, including nephrotoxic and

neurotoxic events [14]. Frequently, cisplatin is administered in combination with other drugs [14]. There have

been several studies aimed at nding drugs able to

potentiate the antiproliferative eect of cisplatin without

increasing the already serious side eects, but the search

has not been successful.Among the chemosensitizer drugs, antiestrogens such

as tamoxifen and ICI 182,780 have been used to modulate the cytotoxic activity of antineoplastic agents such

as doxorubicin and paclitaxel. Resistance to these drugs