COX-2 specific inhibitors enhance the cytotoxic effects of pemetrexed in mesothelioma cell lines.
BACKGROUND
Although malignant pleural mesothelioma is a rare tumour, its incidence is increasing. The prognosis remains very poor with an average survival of 10 months from diagnosis. The choice of chemotherapy regimens for mesothelioma patients is limited and new approaches are required. COX-2 inhibition induces apoptosis in a variety of tumour cell lines. The cytotoxic effect of conventional drugs may be enhanced by the addition of a COX-2 inhibitor. In order to identify possible new therapeutic approaches we aimed to determine whether the addition of COX-2 inhibitors would enhance the cytotoxic effect of chemotherapeutic agents in mesothelioma cell lines.


METHODS
Three mesothelioma cell lines MSTO-211H, NCI-H2052 and NCI-H2452 were utilised. Using the COX-2 positive A549 lung cancer cell line as control, all cell lines were assayed using an MTT assay with non-specific COX-2 inhibitors (sulindac and flurbiprofen), specific COX-2 inhibitors (DuP-697 and NS-398), and chemotherapeutic agents (cisplatin, vinorelbine and pemetrexed).


RESULTS
All cell lines exhibited COX-2 expression by western blotting using two antibodies. The addition of either DuP-697 or NS-398 increased the sensitivity to pemetrexed in all cell lines.


CONCLUSIONS
These findings suggest that the design of novel pemetrexed-containing combination regimens with increased cytotoxicity may be feasible.
O'Kane
Sara L
SL
Postgraduate Medical Institute of the University of Hull and the Hull York Medical School, University of Hull, UK.
Eagle
Gina L
GL
Greenman
John
J
Lind
Michael J
MJ
Cawkwell
Lynn
L
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D004357:Drug Synergism; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
D052246:Cyclooxygenase 2 Inhibitors; D005971:Glutamates; D000068437:Pemetrexed; D014747:Vinblastine; D006147:Guanine; D002945:Cisplatin; D000077235:Vinorelbine