Antibody-penicillin-V-amidase conjugates kill antigen-positive tumor cells when combined with doxorubicin phenoxyacetamide

Cancer Immunol Immunother. 1990;31(4):202-6. doi: 10.1007/BF01789169.


The two monoclonal antibodies (mAb), L6 (anti-carcinoma), and 1F5 [anti-(B-cell-lymphoma)], were chemically linked to the enzyme penicillin-V amidase (PVA), which hydrolyzes phenoxyacetamides, to explore the potential of using mAb-enzyme conjugates for the localization of chemotherapeutic drugs at tumor cells. The phenoxyacetamide derivatives of doxorubicin and melphalan were prepared, yielding the less toxic amides, doxorubicin-N-p-hydroxyphenoxyacetamide (DPO) and melphalan-N-p-hydroxyphenoxyacetamide (MelPO). These were hydrolyzed by PVA to doxorubicin and melphalan respectively. In vitro studies with the L6-positive lung carcinoma cell line, H2981, and the 1F5-positive B-cell lymphoma line, Daudi, showed that DPO was 80-fold less toxic to H2981 cells and 20-fold less toxic to Daudi cells than doxorubicin, and its toxicity was substantially increased when the H2981 cells were pretreated with L6-PVA or the Daudi cells were pretreated with 1F5-PVA. The cytotoxic effect was antigen-specific, since only the binding mAb-enzyme conjugate increased the cytotoxicity of the prodrug. MelPO was more than 1000-fold less toxic than melphalan to H2981 cells and more than 100-fold less toxic than melphalan to Daudi cells. Pretreatment with the mAb-PVA conjugates did not enhance the toxicity of MelPO in either cell line, because PVA hydrolyzes the phenoxyacetamide bond of MelPO too slowly to generate a toxic level of melphalan.

MeSH terms

  • Amidohydrolases / pharmacology*
  • Antibodies, Monoclonal
  • Antigens, Neoplasm / immunology
  • Carcinoma / drug therapy
  • Carcinoma / immunology
  • Carcinoma / pathology
  • Doxorubicin / analogs & derivatives
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacology
  • Doxorubicin / therapeutic use
  • Humans
  • Immunotoxins / chemical synthesis
  • Immunotoxins / pharmacology*
  • Lymphoma / drug therapy
  • Lymphoma / immunology
  • Lymphoma / pathology
  • Melphalan / analogs & derivatives
  • Melphalan / metabolism
  • Melphalan / pharmacology
  • Penicillin Amidase / pharmacology*
  • Penicillin V / pharmacology
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Tumor Cells, Cultured / drug effects*


  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Immunotoxins
  • Prodrugs
  • doxorubicin-N-4-hydroxyphenoxyacetamide
  • melphalan-N-4-hydroxyphenoxyacetamide
  • Doxorubicin
  • Amidohydrolases
  • Penicillin Amidase
  • Melphalan
  • Penicillin V