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 l eukemia/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 doxor ubicin or etoposide using the lymphoma cell line Namalwa and a P-glyco protein-expressing cell line, Namalwa/mdr-1, obtained by retroviral in fection 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 obse rved. In xenografts of Namalwa/mdr-1 cells in severe combined immunode ficiency (SCID) mice, doxorubicin and etoposide at their maximum toler ated 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 mu g/kg) followed by treatment with doxorubicin or etoposide significant ly increased the life span of the mice by 129% and 115%, respectively. After treatment with anti-B4-bR, the Namalwa/mdr-1 population express ed lower levels of P-glycoprotein, and this decrease may account for t he synergistic action of the drug combinations. These results suggest that anti-B4-bR could be used to good effect in combination with curre nt treatment regimens and further hint at a promising role for this im munotoxin in treatment of disease at the minimal residual disease stag e, where cells may be resistant to chemotherapy. (C) 1995 by The Ameri can Society of Hematology.