Anti-B4-blocked ricin synergizes with doxorubicin and etoposide on multidrug-resistant and drug-sensitive tumors.
Anti-B4-blocked ricin (anti-B4-bR) is an immunotoxin directed against CD19-positive cells that is currently being tested in several B-cell leukemia/lymphoma clinical trials. To explore the possibility of using anti-B4-bR in combination with chemotherapy protocols, we investigated the in vitro and in vivo cytotoxic effects of combining it with doxorubicin or etoposide using the lymphoma cell line Namalwa and a P-glycoprotein-expressing cell line, Namalwa/mdr-1, obtained by retroviral infection of Namalwa cells with the mdr-1 gene. Namalwa/mdr-1 cells were slightly more sensitive to anti-B4-bR than Namalwa cells; IC37 values were approximately 4 pmol/L and 8 pmol/L, respectively. When anti-B4-bR was combined simultaneously with doxorubicin or etoposide, additive to supra-additive killing of Namalwa and Namalwa/mdr-1 cells was observed. In xenografts of Namalwa/mdr-1 cells in severe combined immunodeficiency (SCID) mice, doxorubicin and etoposide at their maximum tolerated doses (3 mg/kg x 3 or 15 mg/kg x 3) showed no therapeutic effect. However, treatment with 5 daily bolus injections of anti-B4-bR (50 micrograms/kg) followed by treatment with doxorubicin or etoposide significantly increased the life span of the mice by 129% and 115%, respectively. After treatment with anti-B4-bR, the Namalwa/mdr-1 population expressed lower levels of P-glycoprotein, and this decrease may account for the synergistic action of the drug combinations. These results suggest that anti-B4-bR could be used to good effect in combination with current treatment regimens and further hint at a promising role for this immunotoxin in treatment of disease at the minimal residual disease stage, where cells may be resistant to chemotherapy.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage*; D005838:Genotype; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D051379:Mice; D016513:Mice, SCID; D012276:Ricin / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018941:Antigens, CD19; D000922:Immunotoxins; D005047:Etoposide; D004317:Doxorubicin; D012276:Ricin