Genetic predictors of toxicity from cancer chemotherapy

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Genetic predictors of toxicity from cancer
chemotherapy

• William E Evans
• St. Jude Childrens Research Hospital

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Its not all in the genes!!
E. Vessell
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Genetic polymorphisms of drug disposition and
drug targets

• Growing list of published examples
• 25 Drug metabolizing enzymes
• 7 Drug transporters
• 25 Drug targets and response modifiers
• Evans Relling, Science, 1999.
• Evans McLeod, NEJM, 2003
• Weinshilboum, NEJM 2003
• Evans Relling, Nature, 2004
• Eichelbaum, et al, Ann Rev Medicine, 2006

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Do SNPs in candidate genes relate to toxicity?
Pharmacogenetics of ALL Chemotherapy SJCRH Total
13B (N246)
Do SNPs in candidate genes relate to efficacy?
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TPMT genetic polymorphism determines
mercaptopurine (6MP) metabolism. Our cancer
prototype
Enzyme Activity in Humans. High
Medium Low
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We do know mechanism for loss of
function Variant proteins are rapidly
degraded.
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Active MP metabolites (TGN) determined by TPMT
phenotype
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95 Concordance between TPMT genotype and
phenotype
Disclosure US Patent (1995) for
molecular diagnostics (genotyping) based on these
3 TPMT SNPs and alleles.
Yates, Krynetski, Loennechen, Fessing, Tai, Pui,
Relling, Evans, Ann. Int. Med 12608-14, 1997

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Risk of hematological toxicity related to TPMT
genotype
Relling et al, JNCI, 1999
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Dosing 6MP without pharmacogenetics