Anti-tumour activity of a panel of taxanes toward a cellular model of human cervical cancer |
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Authors: | Daniela Gallo Cristiano Ferlini Mariagrazia Distefano Fabio Cantelmo Cristiana Gaggini Andrea Fattorossi Antonella Riva Ezio Bombardelli Enricos Proietti Salvatore Mancuso Giovanni Scambia |
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Institution: | (1) Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynaecology, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, I-00168 Rome, Italy Tel.: +39-06-35508736; Fax: +39-06-35508736 e-mail: giovanni.scambia@agora.it, IT;(2) Indena, Spa, Milan, Italy, IT;(3) Istituto Superiore Sanità, Department of Virology, Rome, Italy, IT |
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Abstract: | Using a model of human cervical cancer (ME-180 cells), the anti-tumour activity of paclitaxel was compared to that of docetaxel
and IDN5109, a newly developed taxane. The growth inhibition effect of taxanes was assessed after 3 days of exposure. DNA
analysis, the taxane-dependent modulation of the expression of the α and β subunits of tubulin and DNA fragmentation were
assessed by flow cytometry. The presence of apoptosis was confirmed by morphological analysis using a laser scan cytometer.
For the evaluation of “in vivo” anti-tumour activity, taxanes were administered to nude mice intravenously once daily, according
to a q3/4d × 4 schedule. Docetaxel, IDN5109 and paclitaxel obtained “in vitro” IC50 values of 0.86, 1.4 and 2.4 nM, respectively. DNA analysis demonstrated a transient block at the G2/M phase of the cell cycle only after 12 h of culture in the presence of taxanes and an increase of nuclear fragmentation
suggestive for apoptosis after additional 12 and 60 h of exposure. Morphological analysis confirmed the presence of apoptosis.
Taxanes induced a down-modulation of the α subunit of tubulin in the G0/1 phase of the cell cycle, and an overexpression of the β subunit in the G2/M phase. A strong anti-tumour activity was obtained “in vivo” for nude mice xenografted using ME-180 cells (T/C=0% for all
drugs). These data indicate that the three taxanes are strongly active both “in vitro” and “in vivo” toward ME-180 cells.
Clinical studies are now needed to ascertain if the higher anti-tumour activity observed “in vitro” using docetaxel and IDN5109
yields a better clinical response in advanced cervical carcinoma with respect to paclitaxel.
Received: 4 May 1999 / Accepted: 9 July 1999 |
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Keywords: | Taxanes Cervical cancer Apoptosis Tubulin |
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