Combined antitumor therapy with the chemotherapeutic drug doxorubicin and an anti-transferrin receptor immunotoxin: in vitro and in vivo studies.

We have determined the in vitro and in vivo efficacy of the combination of doxorubicin and an anti-transferrin receptor-monoclonal antibody (MAb)-ricin A chain immunotoxin. These agents both possess antineoplastic activity and their differing mechanisms of action and toxicities suggest that they may work well in combination. In vitro cytotoxicity was assayed by the inhibition of both 3H-leucine and 3H-thymidine incorporation into H-MESO-1 human malignant mesothelioma cells. In vivo, tumoricidal activity was determined by the effect of treatment on the survival of nude mice bearing H-MESO-1 as an intraperitoneal xenograft. The effect of doxorubicin on the antitumor activity of immunotoxin was directly compared to that of monensin, a well-described immunotoxin potentiator. The coincubation of doxorubicin (1 microM) with immunotoxin in vitro produced no increase in cytotoxicity or rate of cell kill when compared to immunotoxin alone. The addition of monensin to immunotoxin produced a significant increase in both cytotoxicity and the rate of cell kill. In animal trials, all treated groups demonstrated a significant increase in median survival when compared to controls. Treatment with doxorubicin or immunotoxin produced a mean survival time (MST) of 22 and 23 days, respectively, vs. control MST of 10 days. The combination of immunotoxin and doxorubicin increased the MST to 31 days (p = 0.004 vs immunotoxin or doxorubicin alone). Immunotoxin combined with monensin emulsion produced an increase in survival equivalent to doxorubicin/immunotoxin. The use of all three agents produced an additional improvement in survival. Combinations of standard chemotherapeutic drugs and ricin A chain immunotoxins may have additive antitumor effects in the therapy of solid tumors.