Mesothelioma Articles

Antisense oligonucleotides chemosensitize mesothelioma cells in culture

Source: Cancer Source

Publish Date: 08/15/2003

NEW YORK (Reuters Health) - Antisense oligonucleotides targeting the anti-apoptotic proteins Bcl-2 and Bcl-xL induce apoptosis of mesothelioma cells in culture and sensitize them to chemotherapy, according to a report in the August 20th International Journal of Cancer.

Bcl-2 and Bcl-xL are expressed in a majority of solid tumors, the authors explain, and antisense oligonucleotides targeting them have been shown to facilitate apoptosis in various tumor types.

Dr. Sally Hopkins-Donaldson and associates from University Hospital Zurich in Switzerland investigated the ability of the Bcl-xL-specific antisense oligonucleotide 4529 and the Bcl-2/Bcl-xL-bispecific antisense oligonucleotide 4625 to facilitate apoptosis and sensitize various mesothelioma cell lines to chemotherapy.

Both oligonucleotides downregulated Bcl-2 and Bcl-xL expression in mesothelioma cells, the authors report, whereas only 4625 decreased the Bcl-2 protein level. Neither oligonucleotide affected the expression of other apoptosis-related genes after 6 hours of transfection.

There was a marked decrease in cell viability after exposure to either oligonucleotide, the report indicates, with maximum drops in mitochondrial transmembrane potential (a measure of apoptosis) occurring earlier after 4625 (20 hours) than after 4529 (44 hours) treatment.

The combination of antisense oligonucleotides with cisplatin or gemcitabine induced greater caspase-3-like activity than did either chemotherapeutic agent alone, the researchers note. "Use of antisense oligonucleotides targeting anti-apoptosis proteins Bcl-2 and Bcl-xL successfully lowers the apoptotic threshold in malignant pleural mesothelioma (MPM) cells and sensitizes them to chemotherapy," Dr. Hopkins-Donaldson told Reuters Health.

The combination of 4625 and cisplatin was synergistic against mesothelioma cells over a broad range of cytotoxicities, the investigators found, whereas the combination of 4529 and cisplatin or either oligonucleotide with gemcitabine was predominantly additive.

"We plan to test these antisense oligonucleotides in a nude mouse xenograft model -- where MPM cells are either injected subcutaneously or intraperitoneally, and combinations of antisense oligonucleotides and chemotherapeutic drugs are injected intraperitoneally," Dr. Hopkins-Donaldson said.

"Our antisense oligonucleotides are second generation, and should therefore be more specific with fewer side effects. No toxicity was observed for the 4625 or 4259 after intraperitoneal injection in nude mice," Dr. Hopkins-Donaldson added.

MIRG.org 1-888-802-6376 e-mail

www.MIRG.org • Site Map • About Us • Contact Us • Links • Disclaimer