Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients.

Gupta, Elora; Mick, Rosemarie; Ramı́rez, Jacqueline; Wang, Xiaolin; Lestingi, Timothy M.; Vokes, Everett E.; Ratain, Mark J.

doi:10.1200/jco.1997.15.4.1502

Cited by 173 publications

(102 citation statements)

References 32 publications

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“…␤-Actin cDNA was labeled using random primers with [␣-32 P]CTP (3,000 Ci/mM). In Situ Hybridization-In situ hybridization to mRNA was carried out with each unique 5Ј region (from nucleotide 1 to 320) that contains from 10 to 26% differences between UGT1A7 through UGT1A10 cDNAs for sense or antisense riboprobe labeled with [␣- 35 S]CTP (1500 Ci/mM). Riboprobes were alkali-hydrolyzed generating, on average, 100 -200-nucleotide hybridizing fragments and washed under high stringency at 60°C.…”

Section: Methodsmentioning

confidence: 99%

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Basu¹,

Ciotti²,

Hwang

et al. 2004

Journal of Biological Chemistry

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UDP-glucuronosyltransferase (UGT) isozymes detoxify metabolites, drugs, toxins, and environmental chemicals via conjugation to glucuronic acid. Based on the extended UGT1 locus combined with Northern blot analysis and in situ hybridization, we determined the distribution of UGT1A1 and UGT1A7 through UGT1A10 mRNAs and found them for the first time segmentally distributed in the mucosal epithelia layer of the gastrointestinal tract. Biochemically, recombinant isozymes exhibited pH optima of 5.5, 6.4, 7.6, 8.5, and/or a broad pH range, and activities were found to be unaffected or progressively inhibited by increasing substrate concentrations after attaining V max for certain chemicals. Under different optimal conditions, all exhibited wide substrate selections for dietary and environmentally associated chemicals. Evidence also suggests tandem effects of isozymes in the time for completion of reactions when comparing short-and long-term incubations. Moreover, treatment of colon cells with certain dietassociated constituents, curcumin and nordihydroguaiaretic acid, reversibly targets UGTs causing inhibition without affecting protein levels; there is no direct inhibition of control UGT using curcumin as substrate in the in vitro assay. In summary, we demonstrate that UGTs are located in gastrointestinal mucosa, have vast overlapping activities under differential optimal conditions, and exhibit marked sensitivity to certain dietary substrates/constituents, representing a first comprehensive study of critical properties concerning glucuronidating isozymes in alimentary tissues. Additionally, the highly dynamic, complex, and variable properties necessarily impact absorption of ingested chemicals and therapeutic drugs.The gastrointestinal (GI) 1 system has the critical function of absorbing nutrients from the diet and, simultaneously, acting as a barrier to ingested toxins and unwanted chemicals. To this end, the human UGT1 complex locus, which encodes multiple UDP-glucuronosyltransferase (UGT) isozymes distributed in the GI tract, participates in the broad and critical function of detoxifying lipid-soluble phenols derived metabolically or ingested as part of the diet, its contaminants, and as medications. UGT conjugates glucuronic acid to the acceptor substrate, converting the lipophile to an inactive glucuronide that undergoes facilitated excretion. The isozymes metabolize endogenous substrates such as bilirubin, steroids, bile acids, retinoic acid, and thyroid hormones. Equally important, isozymes also metabolize four categories of dietary phytochemicals that could pose risks for humans and animals when absorbed in excess. Highly abundant dietary flavonoids found in plants are shown to inhibit aromatase (1), and less abundant anthraquinones and two types of phytoestrogens (2-4) can also cause cellular damage. Particular anthraquinones were mutagenic when bioactivated (3) and were carcinogens in long-term feeding experiments in mice (5). Injurious effects of diets were demonstrated by extensive lesions in the reprodu...

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Section: Methodsmentioning

confidence: 99%

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Basu¹,

Ciotti²,

Hwang

et al. 2004

Journal of Biological Chemistry

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“…[13][14][15] While the primary selective pressure for UGT1A enzyme function may have been metabolism of endogenous molecules, UGT1A function is necessary for elimination of exogenous compounds such as the anti-cancer drug irinotecan. [16][17][18] The same common UGT1A1 variants associated with mild elevations of serum bilirubin are associated with diminished in vitro glucuronidation of the active irinotecan metabolite, SN-38, [19][20][21][22] and prolonged exposure and increased toxicity in patients receiving this agent. [23][24][25] As shown by Sai et al, 25 re-sequencing of the UGT1A1 gene in 85 Japanese patients treated with irinotecan confirmed that the haplotypes containing lower expression variants were associated with both a low SN-38G/SN-38 AUC ratio and elevated pretreatment bilirubin concentration.…”

Section: Introductionmentioning

confidence: 99%

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

et al. 2005

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Common polymorphisms within the human UGT1A gene locus are associated with irinotecan and tranilast toxicity. To uncover additional functional variation across this gene cluster, cross-species sequence comparisons were performed. Evolutionarily conserved segments (a total of 47.1 kb) were re-sequenced in 24 African-American, 24 European-American, and 24 Asian individuals, and 381 segregating sites (including 123 singletons) were identified. Highly conserved coding sites were less likely to be polymorphic than diverged sites (Po0.0001) but this pattern was not observed at noncoding sites (P ¼ 0.1025). Among coding variants, the distribution of those computationally predicted to affect function was skewed toward low frequencies. Some alleles occurred at similar frequencies in each population; others had wide disparities. Although strong linkage disequilibrium was detected among the hepatically expressed genes, the degree of linkage disequilibrium varied among populations. These results suggest that rare functional gene variants and inter-population variability must be considered in the interpretation of association studies between UGT1A and drug metabolism/toxicity phenotypes.

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“…Previous studies demonstrated the feasibility and interest of higher doses of irinotecan in patients as monotherapy (7,14) or in combination with 5FU: FOLFIRI regimen (8). The important interpatient variability for irinotecan pharmacokinetic can be, at least partly, explained by the UGT1A1 Ã 28 polymorphism (15).…”

Section: Discussionmentioning

confidence: 99%

High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study

Manfrédi

Bouché

Rougier

et al. 2015

Molecular Cancer Therapeutics

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High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 Ã 1/ Ã 1 (group 1) or Ã 1/ Ã 28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if 7 patients exhibited an objective response (OR) and/or !3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8%

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Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients.

Cited by 173 publications

References 32 publications

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Differential and Special Properties of the Major Human UGT1-encoded Gastrointestinal UDP-glucuronosyltransferases Enhance Potential to Control Chemical Uptake

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

High-Dose FOLFIRI plus Bevacizumab in the Treatment of Metastatic Colorectal Cancer Patients with Two Different UGT1A1 Genotypes: FFCD 0504 Study

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