Host thiopurine methyltransferase status affects mercaptopurine antileukemic effectiveness in a murine model.
BACKGROUND
Thiopurines are used for many cancers, including acute lymphoblastic leukemia (ALL). Patients with an inherited host defect in thiopurine methyltransferase (TPMT) are at high risk for life-threatening toxicity if treated with conventional dosages, but the impact on antileukemic efficacy is less clear.


METHODS
We treated thiopurine-sensitive BCR-ABL+Arf-null Tpmt+/+ ALL in Tpmt+/+, +/-, or -/- recipient mice to test the impact of the host polymorphism on antileukemic efficacy.


RESULTS
Median survival was similar in untreated mice of different Tpmt genotypes (16-18 days). However, in mice treated with low-dose mercaptopurine (such as tolerated by TPMT-/- patients), the difference in 30-day leukemia-free survival by Tpmt genotype was profound: 5% (±9%) for Tpmt+/+ mice, 47% (±26%) for Tpmt+/- mice, and 85% (±14%) for Tpmt-/- mice (P=5×10), indicating a substantial impact of host Tpmt status on thiopurine effectiveness. Among Tpmt+/+ recipient mice, leukemia-free survival improved with higher doses of mercaptopurine (similar to doses tolerated by wild-type patients) compared with lower doses, and at higher doses was comparable (P=0.6) to the survival of Tpmt-/- mice treated with the lower dose.


CONCLUSIONS
These findings support the notion that germline polymorphisms in Tpmt affect not only host tissue toxicity but also antitumor effectiveness.
Departments of aPharmaceutical Sciences bPathology cBiostatistics dOncology, St Jude Children's Research Hospital (Current address Puma Biotechnology Inc., Los Angeles, CA 90024, USA) eDepartment of Tumor Cell Biology, Howard Hughes Medical Institute, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Laura B
LB
Ramsey
Laura J
LJ
Janke
Mathew J
MJ
Edick
Cheng
C
Cheng
Richard T
RT
Williams
Charles J
CJ
Sherr
William E
WE
Evans
Mary V
MV
Relling
D000818:Animals; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D005854:Germ Cells; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000633:toxicity*; D008780:Methyltransferases / Q000235:genetics*; D051379:Mice; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D016044:Fusion Proteins, bcr-abl