Methods for predicting irinotecan toxicity
The present invention concerns the methods and compositions for evaluating the risk of ironotecan toxicity in a cancer patient based on the genotype of the patient at position −3156 of the UGT1A1 gene or at any position in linkage disequilibrium with the −3156 variant.
1. A method for evaluating the risk of irinotecan toxicity in a cancer patient being considered for irinotecan therapy comprising:
obtaining a nucleic acid sample from the patient; and
determining from the sample the nucleotide sequence at position −3156 in one or both UGT1A1 genes of the patient, wherein determination of an adenine residue at position −3156 in one or both UGT1A1 genes indicates the patient is at risk for irinotecan toxicity.
2. The method of claim 1 , further comprising classifying the UGT1A1 activity level in the patient, whereby identification of a guanine residue indicates the patient does not have a low level of activity.
3. The method of claim 1 , wherein the nucleotide sequence at position −3156 is determined for one UGT1A1 gene.
4. The method of claim 1 , wherein the nucleotide sequence at position −3156 is determined for both UGT1A1 genes in the patient.
5. The method of claim 1 , further comprising analyzing a glucuronidation rate associated with a sequence at position −3156 in one or both UGT1A1 genes.
6. The method of claim 1 , further comprising optimizing a dose of irinotecan for administration to the patient.
7. The method according to claim 1 , wherein determining the sequence at position −3156 in one or both UGT1A1 genes is performed by a hybridization assay.
8. The method according to claim 1 , wherein determining the nucleotide sequence at position −3156 of a UGT1A1 gene or genes is performed by a sequencing or microsequencing assay.
9. The method according to claim 1 , wherein determining the nucleotide sequence at position −3156 of a UGT1A1 gene or genes is performed by an allele-specific amplification assay.
10. The method of claim 1 , further comprising administering to the patient irinotecan.
11. The method of claim 10 , further comprising administering to the patient a second agent to reduce excretion of an active irinotecan species through the bile.
12. A method for evaluating the risk of irinotecan toxicity in a cancer patient being considered for irinotecan therapy comprising:
obtaining a nucleic acid sample from the patient; and,
sequencing the sample to determine the nucleotide sequence at position −3156 in one or both UGT1A1 genes of the patient, wherein identification of an adenine residue at position −3156 in one or both UGT1A1 genes indicates the patient is at risk for irinotecan toxicity.
13. The method of claim 12 , further comprising classifying the UGT1A1 activity level in the patient, whereby identification of a guanine residue indicates the patient does not have a low level of activity.
14. The method of claim 12 , further comprising administering irinotecan to the patient if a guanine nucleotide is found at position −3156.