|
|
Antitumor activity of
imatinib mesylate in medulloblastoma cell lines and xenografts
R. Morosetti, D. Meco, C. Dominici, T. Servidei, A. Riccardi, A. M. Di
Francesco, G. Cusano, R. Riccardi
Catholic University, Rome, Italy; La Sapienza University, Rome,
Italy.
Background.
Medulloblastoma (MB) is the most common pediatric malignant
brain tumor.
Its tendency to disseminate is the main cause of treatment failure.
Recently PDGFRa has been suggested to play a role in MB metastasis.
Imatinib mesylate (STI571, Gleevec) is an inhibitor of selected receptor
tyrosine kinases, including PDGFRa/ß and c-kit.
Thus, we investigated the therapeutic potential of STI571 in MB, by evaluating
its antitumor activity in vitro and in vivo.
Methods.
Expression of PDGFRa/ß and c-kit was studied in 4 human MB/PNET
cell lines (D283 Med, D341 Med, DAOY, PFSK) by RT-PCR and western
blotting.
We performed growth inhibition assays at different STI571concentrations (5 to 50
µM)and time-points.
The antitumor activity of STI571 was studied in D283 Med xenografts in nude
mice, either by treating palpable tumors or by trying to prevent tumor
development after inoculation.
STI571 was administrated p.o. (100, 200 and 400 mg/kg/day) twice a day for 5
consecutive days for two weeks.
Results.
All cell lines expressed PDGFRa and c-kit, while only DAOY and
PFSK expressed PDGFRß mRNA and protein.
STI571 produced a dose- and time-dependent inhibition of growth of all the cell
lines, although with a different sensitivity (IC50 ranging from 7 to
13 µM).
In the therapeutic study, STI571 was inactive or marginally active against D283
xenografts, while in the prevention study a significant difference in tumor size
was seen between treated and control animals on day 22 (TWI>60).
No obvious toxicity was observed.
Conclusions.
STI571 was able to inhibit the in vitro growth of 4
MB cell lines and this was associated with a significant antitumor activity in
vivo, thus suggesting a therapeutic potential of STI571 in MB.
Whether these effects are mediated through inhibition of PDGFR or c-kit is under
evaluation.
(Supported by Italian Ministry of Health; AIRC; FOP and ALTI).
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-001921,00.asp
|
