Search

BACKGROUND: In vitro data suggest that the growth of rhabdomyosarcoma (RMS) cells is suppressed in a concentration-dependent manner by 4-hydroxycyclophosphamide (4HCY), the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY). Various retrospective studies on the relationship between genes encoding proteins involved in the formation and elimination of 4HCY (i.e., 4HCY pharmacokinetics) and cyclophosphamide (CY) efficacy and toxicity have been conflicting. PROCEDURES: We evaluated germline pharmacogenetics in 262 patients with newly diagnosed intermediate-risk RMS who participated in one prospective Children’s Oncology Group clinical trial, ARST0531. Patients were treated with either vincristine/actinomycin/cyclophosphamide (VAC) or VAC alternating with vincristine/irinotecan (VAC/VI). We analyzed the associations between event-free survival and 394 single-nucleotide polymorphisms (SNP) in 14 drug metabolizing enzymes or transporters involved in 4HCY pharmacokinetics. RESULTS: Eight SNPs were associated (p-value < .05 by univariate analysis) with 3-year event-free survival; no SNPs survived a false discovery rate < 0.05. CONCLUSIONS: Our data suggest that a pharmacogenomic approach to therapy personalization of cyclophosphamide in intermediate-risk rhabdomyosarcoma is not viable. Other methods to personalize therapy should be explored.

Nonsteroidal anti-inflammatory drugs (NSAIDs) target the prostaglandin H synthase enzymes, cyclooxygenase (COX)-1 and COX-2, and reduce colorectal cancer risk. Genetic variation in the genes encoding these enzymes may be associated with changes in colon and rectal cancer risk and in NSAID efficacy.We genotyped candidate polymorphisms and tag SNPs in PTGS1 (COX-1) and PTGS2 (COX-2) in a population-based case–control study (Diet, Activity and Lifestyle Study, DALS) of colon cancer (n = 1,470 cases/1,837 controls) and rectal cancer (n = 583/775), and independently among cases and controls from the Colon Cancer Family Registry (CCFR; colon n = 959/1,535, rectal n = 505/839).In PTGS2, a functional polymorphism (-765G[C; rs20417) was associated with a twofold increased rectal cancer risk (p = 0.05) in the DALS. This association replicated with a significant nearly fivefold increased risk of rectal cancer in the CCFR study (ORCC vs. GG = 4.88; 95 % CI 1.54–15.45; ORGC vs. GG = 1.36; 95 %CI 0.95–1.94). Genotype–NSAID interactions were observed in the DALS for PTGS1 and rectal cancer risk and for PTGS2 and colon cancer risk, but were no longer significant after correcting for multiple comparisons and did not replicate in the CCFR. No significant associations between PTGS1 polymorphisms and colon or rectal cancer risk were observed.

In vivo, aspirin (acetylsalicylic acid) is rapidly deacetylated to form salicylic acid, which then undergoes primary or secondary glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs). The variant UGT1A6*2 (T181A, R184S) is associated with altered enzyme function. Our objective was to compare salicylic acid glucuronidation in individuals with different UGT1A6 genotypes.Following orally dosing with 650 mg aspirin, saliva and urine samples were collected over a period of 24 h from healthy individuals with homozygous wild-type UGT1A6 *1/*1 (n=19) and homozygous variant UGT1A6 *2/*2 (T181A, R184S) (n=9) genotypes.No statistically significant differences were observed in salivary pharmacokinetic parameters. Urinary excretion of the sum of aspirin and its metabolites (salicyluric acid, salicyluric acid phenolic glucuronide, salicyl phenolic glucuronide, salicyl acyl glucuronide, salicylic acid) during the early period of 2-4 h of collection was significantly lower in UGT1A6 *1/*1 than in UGT1A6 *2/*2 individuals. Further, UGT1A6 *1/*1 individuals excreted a lower percentage of aspirin and its metabolites in the first 12 h and a greater percentage after 12 h than UGT1A6 *2/*2 individuals.The variant UGT1A6*2 or polymorphisms in other UGTs that are in linkage disequilibrium with UGT1A6*2 may confer more rapid glucuronidation of salicylic acid than the wild-type UGT1A6 *1/*1.

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk of colorectal adenomas and cancer. NSAIDs, including aspirin, target the prostaglandin H synthases, COX-1 and COX-2, which convert arachidonic acid into prostaglandins. We examined tagSNPs and candidate polymorphisms in COX-1 and COX-2 in relation to colorectal neoplasia risk and potential interactions with NSAID use. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in PTGS1 (COX-1) and PTGS2 (COX-2) representative of common genetic variation in Europeans. Including candidate polymorphisms, we genotyped 18 SNPs in PTGS1 and 17 SNPs in PTGS2. SNPs were genotyped on the same Illumina platform in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma and cancer cases. We investigated these SNPs in relation to the risk of colorectal neoplasia and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424) vs. controls (n=1780), rectal cancer (n=583) vs. controls (n=775), and colorectal adenoma (n=485) vs. controls (n=578). For single SNP associations, multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (>90% of all study populations). No correction was made for multiple testing. Results: There were no main associations with PTGS1 tagSNPs or candidate polymorphisms (R8W, P17L and L237M) and colorectal neoplasia risk. Although not statistically significant, the L15-L16 deletion allele showed a trend towards increased risk for both colon and rectal cancer, consistent with the previously reported increased adenoma risk. In PTGS2, a rare 5′ tagSNP (rs4648250, −1877A>G, MAF=1%) was associated with a marginally decreased risk of both rectal (OR: 0.24, 95% CI: 0.05-1.08) and colon cancer (OR: 0.63, 95% CI: 0.36-1.10). NSAID use is known to reduce the risk of colorectal neoplasia and all three studies have shown the same protective effect in previous analyses. Interactions between genotypes and NSAID use essentially fell into one of two general categories: a) Individuals with the variant allele lost the protective effect of NSAID use (PTGS1 rs10306110-G, rectal p-interaction=0.02, adenoma p-int=0.08; PTGS2 [rs689466][1]-G, rectal p-int=0.03, colon p-int=0.18; rs20424-G, colon p-int=0.05; [rs689469][2]-A, colon p-int=0.03, rectal p-int=0.09).); and b) Individuals with the variant allele showed stronger protection with by NSAIDs than individuals with the wildtype genotype (PTGS1 rs6478565-G, rs10306135-T, rs10306164-G, rectal p-int=0.01-0.02). Conclusion: These data suggest that a rare 5′ SNP in PTGS2 may predict risk of colorectal cancer and provide further evidence that genetic variability in PTGS1 and PTGS2 may modify the protective association between NSAID and colorectal neoplasia risk, especially for rectal cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5710. [1]: /lookup/external-ref?link_type=GEN&access_num=rs689466&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom [2]: /lookup/external-ref?link_type=GEN&access_num=rs689469&atom=%2Fcanres%2F70%2F8_Supplement%2F5710.atom