Anti-mesothelin immunotoxin SS1P in combination with gemcitabine results in increased activity against mesothelin-expressing tumor xenografts.
OBJECTIVE
To determine the antitumor activity of the anti-mesothelin immunotoxin SS1P in combination with gemcitabine against mesothelin-expressing tumor xenografts.


METHODS
The in vitro activity of SS1P in combination with gemcitabine against the mesothelin-expressing cell line A431/K5 was evaluated using cytotoxicity and apoptosis assays. The antitumor activity of this combination was evaluated in nude mice bearing A431/K5 tumor xenografts. Tumor-bearing mice were treated with different doses and schedules of gemcitabine alone, SS1P alone (0.2 mg/kg i.v. every other day x three doses), or with both agents together, and tumor volumes were measured over time.


RESULTS
In vitro studies failed to show the synergy of SS1P plus gemcitabine against the mesothelin-expressing A431/K5 cells. In contrast, in the in vivo setting, there was a marked synergy when SS1P was combined with gemcitabine for the treatment of mesothelin-expressing tumor xenografts. This synergy was present using different doses and schedules of gemcitabine administration. In mice treated with fractionated doses of gemcitabine in combination with SS1P, complete tumor regression was observed in all mice and was long-lasting in 60% of the animals. Also, this antitumor activity was specific to SS1P because HA22, an immunotoxin targeting CD22 not expressed on A431/K5 cells, did not increase the efficacy of gemcitabine.


CONCLUSIONS
SS1P in combination with gemcitabine results in marked antitumor activity against mesothelin-expressing tumors. This combination could be potentially useful for the treatment of human cancers that express mesothelin and are responsive to gemcitabine therapy.
Hassan
Raffit
R
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, and the Clinical Center, NIH, Bethesda, Maryland 20892, USA. hassanr@mail.nih.gov
Broaddus
V Courtney
VC
Wilson
Shannon
S
Liewehr
David J
DJ
Zhang
Jingli
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D000090204:Mesothelin; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C000715528:Msln protein, mouse; C474515:SS1(dsFv)PE38; D003841:Deoxycytidine; D000090204:Mesothelin; D000093542:Gemcitabine