ABCB1-1Delta polymorphism can predict hematologic toxicity in dogs treated with vincristine.
BACKGROUND
Dogs that harbor the naturally occurring ABCB1-1Delta polymorphism experience increased susceptibility to avermectin-induced neurological toxicosis as a result of deficient P-glycoprotein function. Whether or not the ABCB1-1Delta polymorphism affects susceptibility to toxicity of other P-glycoprotein substrate drugs has not been studied.


OBJECTIVE
Dogs that possess the ABCB1-1Delta mutation are more likely to develop hematologic toxicity associated with vincristine than ABCB1 wild-type dogs.


METHODS
Thirty-four dogs diagnosed with lymphoma were included in this study.


METHODS
Cheek swab samples were obtained from dogs diagnosed with lymphoma that were to be treated with vincristine. DNA was extracted from cheek swabs and the ABCB1 genotype was determined. Hematologic adverse drug reactions were recorded for each dog and graded according to the Veterinary Comparative Oncology Group's criteria for adverse event reporting (Consensus Document). In order to avoid possible bias, ABCB1 genotype results for a particular patient were not disclosed to oncologists until an initial adverse event report had been submitted.


RESULTS
Dogs heterozygous or homozygous for the ABCB1-1Delta mutation were significantly more likely to develop hematologic toxicity, specifically neutropenia (P= .0005) and thrombocytopenia (P= .0001), after treatment with vincristine than ABCB1 wild-type dogs.


CONCLUSIONS
At currently recommended dosages (0.5-0.7 mg/M(2)), vincristine is likely to cause hematologic toxicity in dogs with the ABCB1-1Delta mutation, resulting in treatment delays and unacceptable morbidity and mortality. Assessing the ABCB1-1Delta genotype before vincristine administration and decreasing the dosage may prevent toxicity and treatment delays resulting from neutropenia or thrombocytopenia.
Mealey
K L
KL
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA. kmealey@vetmed.wsu.edu
Fidel
J
J
Gay
J M
JM
Impellizeri
J A
JA
Clifford
C A
CA
Bergman
P J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D004283:Dog Diseases / Q000097:blood / Q000235:genetics*; D004285:Dogs; D020022:Genetic Predisposition to Disease; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D014750:Vincristine / Q000009:adverse effects*
D000970:Antineoplastic Agents; D027361:Organic Anion Transporters; D014750:Vincristine