title: Initial testing of lenalidomide by the pediatric preclinical testing program.
abstract: BACKGROUND
  Lenalidomide, a novel immunomodulatory agent, is reported to modulate stem cell differentiation, and have direct antiproliferative activity as well as inhibit inflammation and hyperalgesia. On the basis of this varied pharmacological profile, lenalidomide is under investigation as a treatment for a range of oncologic indications.
  
  
  METHODS
  Lenalidomide was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1 nM to 10 µM. It was tested against the PPTP in vivo panels at a dose of 30 mg/kg administered orally (PO) once daily for a planned for 6 weeks.
  
  
  RESULTS
  In vitro activity was not observed at concentrations up to 10 µM. Lenalidomide was well tolerated, and induced significant differences in EFS distribution compared to control in 7 of 37 (18.9%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The best response in the solid tumor panel was PD2 [progressive disease with growth delay (EFS T/C > 1.5)], observed in 4 of 37 (10.8%) solid tumor xenografts. A single ALL xenograft showed a PD2 response.
  
  
  CONCLUSIONS
  Direct antiproliferative effects of lenalidomide were not observed in vitro. In vivo lenalidomide demonstrated low activity against tumors in immune-deficient mice. Our results suggest that lenalidomide's utility in the pediatric clinical setting may depend upon its ability to induce antitumor activity through effects on host immune and stromal cells rather than through direct effects on tumor cells.
authors.affiliation: Texas Tech University Health Sciences Center, Lubbock, Texas, USA. patrick.reynolds@ttuhsc.edu
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Billups
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide