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Improved Therapeutic Responses in a Xenograft Model of Human B Lymphoma (Namalwa) for Liposomal Vincristine versus Liposomal Doxorubicin Targeted via Anti-CD19 IgG2a or Fab′ Fragments
Ist Teil von
Clinical cancer research, 2004-02, Vol.10 (3), p.1100-1111
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2004
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
Purpose: Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can
be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs,
vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates.
Experimental Design: SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[αCD19]) or its Fab′ fragments (SIL[Fab′]).
Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded
SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled
liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model.
Results: SIL[αCD19] or SIL[Fab′] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab′]
had longer circulation times than SIL[αCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations
of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with
VCR were superior to those loaded with DXR. SIL[Fab′] had better therapeutic outcomes than SIL[αCD19] for the drug DXR but
were equally efficacious for the drug VCR.
Conclusions: Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high
levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer
circulation times of SIL[Fab′] versus SIL[αCD19] led to superior therapeutics for DXR-loaded immunoliposomes.