title: Synergistic antitumor activity of anti-CD25 recombinant immunotoxin LMB-2 with chemotherapy.
abstract: OBJECTIVE
  Although anti-CD25 recombinant immunotoxin LMB-2 is effective against CD25(+) hairy cell leukemia, activity against more aggressive diseases such as adult T-cell leukemia (ATL) is limited by rapid disease progression between treatment cycles. Our goal was to determine in vivo whether rapid growth of CD25(+) tumor is associated with high levels of tumor interstitial soluble CD25 (sCD25) and whether chemotherapy can reduce tumor sCD25 and synergize with LMB-2.
  
  
  METHODS
  Tumor xenografts expressing human CD25 were grown in mice, which were then treated with LMB-2 and chemotherapy either alone or in combination, and sCD25 level and antitumor activity were measured.
  
  
  RESULTS
  CD25(+) human xenografts growing rapidly in nude mice had intratumoral sCD25 at levels that were between 21- and 2,200 (median 118)-fold higher than in serum, indicating that interstitial sCD25 interacts with LMB-2 in tumors. Intratumoral sCD25 levels were in the range 21 to 157 (median 54) ng/mL without treatment and 0.95 to 6.1 (median 2.6) ng/mL (P < 0.0001) 1 day after gemcitabine administration. CD25(+) xenografts that were too large to regress with LMB-2 alone were minimally responsive to gemcitabine alone but completely regressed with the combination. Ex vivo, different ratios of gemcitabine and LMB-2 were cytotoxic to the CD25(+) tumor cells in an additive, but not synergistic, manner.
  
  
  CONCLUSIONS
  Gemcitabine is synergistic with LMB-2 in vivo unrelated to improved cytotoxicity. Synergism, therefore, appears to be related to improved distribution of LMB-2 to CD25(+) tumors, and is preceded by decreased sCD25 within the tumor because of chemotherapy. To test the concept of combined treatment clinically, patients with relapsed/refractory ATL are being treated with fludarabine plus cyclophosphamide before LMB-2.
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Rajat
authors: R
authors: Singh
authors: Yujian
authors: Y
authors: Zhang
authors: Ira
authors: I
authors: Pastan
authors: Robert J
authors: RJ
authors: Kreitman
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D005098:Exotoxins / Q000627:therapeutic use; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D010954:Plasmacytoma / Q000276:immunology / Q000628:therapy*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; D000922:Immunotoxins; D053645:Interleukin-2 Receptor alpha Subunit; D003841:Deoxycytidine; D000093542:Gemcitabine