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Treatment of Human B-Cell Precursor Leukemia in SCID Mice by Using a Combination of the Anti-CD19 Immunotoxin B43-PAP with the Standard Chemotherapeutic Drugs Vincristine, Methylprednisolone, and L-Asparaginase

1998; Taylor & Francis; Volume: 31; Issue: 1-2 Linguagem: Inglês

10.3109/10428199809057594

1042-8194

Rauf Onur Ek, Paul S. Gaynon, Tamer Zeren, Lisa M. Chelstrom, Dorothea E. Myers, Fatih M. Uckun,

Acute Lymphoblastic Leukemia research

We have compared the antileukemic activity of the investigational biotherapeutic agent B43-PAP to the antileukemic activities of the standard chemotherapeutic drugs vincristine (VCR), methylprednisolone (PDN), L-asparaginase (L-ASP) as single agents as well as in a 3-drug combination regimen ("VPL") using a SCID mouse model of human B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). When mice (N = 95) were challenged with 1 × 106 NALM-6 leukemia cells, all of them died of disseminated leukemia with a median event-free survival (EFS) of 47 ± 6 days. B43-PAP was more active than VCR, PDN, or L-ASP and the two-drug combinations VCR+B43-PAP, PDN+B43-PAP, or L-ASP + B43-PAP were not significantly more active than B43-PAP. The 120 days EFS outcome results were 46 ± 13% for B43-PAP (Median EFS = 92 ± 22 days), 0 ± 0% for VCR (Median EFS = 49 ± 1 days), 40 ± 22% for PDN (Median EFS = 100 ± 20 days), 0 ± 0% for L-ASP (Median EFS = 41 ± 1 days), 60 ± 22% for VCR + B43-PAP (Median EFS = >120 days), 60 ± 22% for PDN + B43-PAP (Median EFS = >120 days), and 50 ± 25% for L-ASP + B43-PAP (Median EFS = 93 ± 27 days), When mice (N = 61) were challenged with 5 × 106 NALM-6 cells, all of them rapidly died of disseminated leukemia with a median EFS of 37 ± 3 days. The 3-drug combination "VPL" (Median EFS = 75 ± 23 days) was slightly less active than B43-PAP (Median EFS = 84 ± 19 days) (P = 0.09). Notably, the combination of "VPL" with B43-PAP (i.e., VPLB) resulted in 100% survival. By comparison, the combination of "VPL" with daunorubicin (i.e., VPLD) (Median EFS = 69 ± 31 days) was not more active than VPL. To our knowledge, this preclinical study is the first to demonstrate the feasibility and superb antileukemic activity of immunochemotherapy using anti-CD 19 immunotoxin in combination with the standard 3-drug combination "VPL" against BCP ALL.