The pediatric preclinical testing program: description of models and early testing results.
BACKGROUND
The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide.


METHODS
Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly.


RESULTS
Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated.


CONCLUSIONS
We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity.
Houghton
Peter J
PJ
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. peter.houghton@stjude.org
Morton
Christopher L
CL
Tucker
Chandra
C
Payne
Debbie
D
Favours
Edward
E
Cole
Claire
C
Gorlick
Richard
R
Kolb
E Anders
EA
Zhang
Wendong
W
Lock
Richard
R
Carol
Hernan
H
Tajbakhsh
Mimi
M
Reynolds
C Patrick
CP
Maris
John M
JM
Courtright
Joshua
J
Keir
Stephen T
ST
Friedman
Henry S
HS
Stopford
Charles
C
Zeidner
Joseph
J
Wu
Jianrong
J
Liu
Tiebin
T
Billups
Catherine A
CA
Khan
Javed
J
Ansher
Sherry
S
Zhang
Jian
J
Smith
Malcolm A
MA
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D014750:Vincristine; D003520:Cyclophosphamide