Mary Relling

..We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes...

..Even when children receiving irradiation were excluded, the incidence was still higher in those receiving G-CSF (P =.019). In the setting of intensive antileukemic therapy, short-term use of G-CSF may increase the risk of t-ML...

..We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype...

..Putative risk factors for osteonecrosis have included being female, white race, and older age. Our goal was to define possible genetic risk factors for osteonecrosis among children treated for newly diagnosed ALL...

..Gaining better insight into the genetic elements of both the patient and the tumour that affect drug efficacy will eventually allow for individualized dosage determination and fewer adverse effects...

..For drugs that are metabolized by enzymes whose genes have clearly inactivating polymorphisms, clinical trial participants should be genotyped for those polymorphisms...

..Most anticonvulsant drugs induce drug-metabolising enzymes and thereby increase the clearance of anticancer agents. We investigated whether anticonvulsants compromise the efficacy of cancer chemotherapy...

..The authors studied the clinical outcome of 106 children with acute lymphoblastic leukemia (ALL) who developed a bone marrow recurrence as the first adverse event after contemporary intensified therapy...

..04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy...

..The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37% +/- 13% 5 year DFS)...

..7%) children with GG genotype, developed osteonecrosis. PAI-1 polymorphisms and PAI-1 serum levels have previously been associated with thrombosis. We conclude that PAI-1 genetic variation may contribute to risk of osteonecrosis...

..Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response...

..026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy...

..86, respectively). CONCLUSION: A pharmacodynamic relationship exists between systemic etoposide exposure and response to therapy when oral etoposide is used as part of remission induction regimens for relapsed or refractory childhood ALL...

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..The authors evaluated the response rate, toxicity, and pharmacokinetics of topotecan given before standard induction therapy for childhood acute lymphoblastic leukemia (ALL) in first relapse...

..We reviewed the outcome of older adolescents (age 15 to 18 years) treated in four consecutive Total Therapy studies to determine if recent improved treatment extended to this high-risk group...

..This study has provided new insights into the intracellular disposition of MTX in leukemia cells and how it affects treatment efficacy...

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..Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse...

..Our goal was to use the information to further refine therapy and advance cure rates...

..Further, the systemic clearance of methotrexate, teniposide, etoposide, and cytarabine did not differ with BMI (P > .3). We conclude that BMI does not affect the outcome or toxicity of chemotherapy in this patient population with ALL...

..Little is known about the incidence of secondary neoplasms after 15 to 20 years in children and adolescents who were treated for acute lymphoblastic leukemia...

..030) and CBR activity expressed as the rate of synthesis of doxorubicinol (p = 0.028). Our findings warrant further studies to evaluate the impact of CBR1 1096G>A genotype status on the variable pharmacodynamics of anthracycline drugs...

..01% or more at the end of the 6-week remission induction phase. Our results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether...

..This intersection of genomics and medicine has the potential to yield a new set of molecular diagnostic tools that can be used to individualize and optimize drug therapy...

..Prednisone strongly induces etoposide clearance, genetic polymorphisms may predict the constitutive and induced clearance of etoposide, and the relationship between genotype and phenotype differs by race...

..We determined the long-term survival and the rates of health insurance coverage, marriage, and employment among patients who had attained at least 10 years of event-free survival...

..Treatment results for acute lymphoblastic leukemia (ALL) clearly have improved over the past decade, but black children have not fared as well as white children in large national trials...

..In the interim, prospective clinical trials have provided valuable clues that are further increasing the cure rate of childhood acute lymphoblastic leukemia...

..This SNP is common (>18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to thiopurines may reflect the greater frequency of this MRP4 SNP...

..One of the adverse effects of glucocorticoids is hypertension. Our aim was to define the frequency of and clinical and genetic risk factors for steroid-induced hypertension...

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..6+/-3.4 nmol/min mg versus NQO1(blacks[NQO1*1/*2])=1.1+/-1.2 nmol/min mg, p=0.134). Our findings pinpoint the presence of significant interethnic differences in polymorphic hepatic NQO1 activity...

..Moreover, asparaginase hastened osteonecrosis, indicating that drugs may interact with glucocorticoids to affect osteonecrosis risk...

..Our aim was to identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL)...

..403), 6.5% vs. 12.5% in blacks (P = 0.508), and 69.6% vs. 75.0% in Hispanics (P= 0.663). Our data do not support an association between common CYP3A4, NQO1 or CYP3A5 polymorphisms and the risk of t-ML in children treated for ALL...

..Taken together, these data suggest that topotecan may be a suitable replacement for etoposide in combination chemotherapy for the treatment of retinoblastoma...

..86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes...

..Increasingly, pharmacodynamic and pharmacogenomic studies are being used to individualize therapy to enhance efficacy and reduce toxicity...

..Dexamethasone is used widely in oncology, but pharmacokinetic studies are lacking. We evaluated dexamethasone pharmacokinetics in children with acute lymphoblastic leukemia...

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..Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX...

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..We conclude that acquired genetic variation in leukemia cells has a stronger influence on MTXPG accumulation than inherited genetic variation...

..Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined...

..Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer...

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..These data suggest that gene expression profiling from accessible tissues may identify targets involved in therapy-related malignancies in unrelated tissues...

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..We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine...

..Together, these findings provide new insights to the intracellular disposition of MTX in human ALL cells, and provides a mechanism-based model for characterizing differences among patients and genetic subtypes of ALL...

..These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism...

..Thus, the single platform of expression profiling should enhance the accurate risk stratification of pediatric ALL patients...

..These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome these potential causes of treatment failure in childhood ALL...

..5%, precision 6.8%) and also performed better than regression methods for abnormally high or low clearances. We conclude that Bayesian estimation with limited sampling gives the best estimates of etoposide clearance...

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..These studies demonstrate a substrate specific functional SNP (452C>T) in the human GGH gene that is associated with lower catalytic activity and higher accumulation of long-chain MTX-PG in leukaemia cells of patients treated with HDMTX...

..Because CRHR1 polymorphisms have been associated with other corticosteroid effects, our goal was to define whether CRHR1 polymorphisms predict which patients with ALL are likely to develop bone mineral deficits...

..These differences provide mechanistic and treatment insights for lineage and ploidy differences in MTXPG accumulation in human leukemia cells in vivo...

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..Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients...

..These findings indicate that etoposide triggers the formation of Mll gene fusions, a critical step for the development of treatment-induced leukemic transformation...

..We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients...

..CONCLUSIONS: Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL...

..009, logistic regression), when comparing "best" and "worst" risk groups. These data are consistent with growing evidence that both acquired and host genetics influence response to cancer therapy...

..Whereas adult t-AML patients are more likely to be (GAA)4/5 heterozygotes, this is not statistically significant, and this polymorphism within the MLL BCR has only a suggestive association with t-AML development...

..To identify children with acute lymphoblastic leukemia (ALL) at initial diagnosis who are at risk for inferior response to therapy by using molecular signatures...

..Therefore, the finding of a physiologic third space during MTX administration combined with the detection of renal dysfunction in the following weeks should be an indication for prolonged therapeutic drug monitoring...

..In summary, we provide functional evidence that SMARCB1 is involved in prednisolone resistance and identified a promoter SNP that alters the level of SMARCB1 mRNA and protein expression and the binding of PARP1 to the SMARCB1 promoter...

..Tumors with increased CYP3A copy number (via amplification or increased chromosome 7q) would be expected to show reduced cytotoxicity to some chemotherapeutic drugs and potentially an increase in the outgrowth of drug resistant tumors...

..Therefore, chromosomal gain can alter the concordance of germline genotype and cancer cell phenotypes, indicating that allele-specific quantitative genotyping may be required to define cancer pharmacogenomics unequivocally...

..5 pmol/5 x 10(6) cells. CONCLUSIONS: This method is suitable for measurement of thiopurine metabolite concentrations in lymphoblasts in children with acute lymphoblastic leukemia following a single dose of intravenous mercaptopurine...

..Our long- term goal is to identify host- and treatment-related risk factors for t-AML so that we can design less leukemogenic anticancer treatment regimens, with improved efficacy for the primary ALL. ..

..Together, these laboratory and clinical studies will elucidate the contribution of pharmacokinetic and metabolic variability as determinants of the disposition and leukemogenic effects of the epipodophyllotoxins in children with cancer. ..

..In this proposal, we will use our knowledge of leukemia therapy and state-of-the-art mouse models to work out schedules of medicines that maintain cure rates for leukemia but are less toxic to bone than current schedules. ..