Anti-tumour activity of a panel of taxanes toward a cellular model of human cervical cancer.
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 alpha and beta 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 x 4 schedule. Docetaxel, IDN5109 and paclitaxel obtained "in vitro" IC(50) values of 0.86, 1.4 and 2.4 nM, respectively. DNA analysis demonstrated a transient block at the G(2)/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 alpha subunit of tubulin in the G(0/1) phase of the cell cycle, and an overexpression of the beta subunit in the G(2)/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.
Gallo
D
D
Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynaecology, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, I-00168 Rome, Italy.
Ferlini
C
C
Distefano
M
M
Cantelmo
F
F
Gaggini
C
C
Fattorossi
A
A
Riva
A
A
Bombardelli
E
E
Proietti
E
E
Mancuso
S
S
Scambia
G
G
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002453:Cell Cycle; D004273:DNA, Neoplasm / Q000187:drug effects; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043823:Taxoids; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000473:pathology*
D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D004273:DNA, Neoplasm; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; C080625:taxane; D017239:Paclitaxel