Host thiopurine methyltransferase status affects mercaptopurine antileukemic effectiveness in a murine model.

Abstract

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.

MATERIALS AND 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.

• Authors: Laura B Ramsey, Laura J Janke, Mathew J Edick, Cheng Cheng, Richard T Williams, Charles J Sherr, William E Evans, Mary V Relling
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 24 Issue 5 Pg. 263-71 (May 2014) ISSN: 1744-6880 [Electronic] United States
• PMID: 24710003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Mercaptopurine
• Methyltransferases
• thiopurine methyltransferase
• Fusion Proteins, bcr-abl

Topics

• Animals
• Fusion Proteins, bcr-abl (genetics)
• Germ Cells
• Humans
• Male
• Mercaptopurine (administration & dosage, toxicity)
• Methyltransferases (genetics)
• Mice
• Polymorphism, Genetic
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, enzymology, pathology)