***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: E7070 is a novel sulfonamide anticancer agent that disrupts the G1/S phase of the cell cycle . The objectives of this phase I study of E7070 were to estismate the maximal tolerated dose ( MTD ) , to determine the recommended dose for phase II , and to clarify the pharmacokinetic profile of E7070 and its relation to polymorphisms of CYP2C9 ( * 2 , * 3 ) and CYP2C19 ( * 2 , * 3 ) in Japanese patients . Patients received 1–2‐h i.v . infusions of E7070 ( 400 , 600 , 700 , 800 or 900 mg/m2 ) on day 1 of a 21‐day cycle . Twenty‐one patients received between one and eight cycles of E7070 . The dose‐limiting toxicities ( DLT ) comprised leukopenia , neutropenia , thrombocytopenia , elevation of aspartate aminotransferase , colitis , and ileus . The mean area under the plasma concentration – time curve ( AUC ) for successive dose levels increased in a non‐dose‐proportional manner . Two patients were heterozygous for the CYP2C9 mutation . For CYP2C19 , eight patients were wild type and the remainder had heterozygous ( n = 8) or homozygous mutations ( n = 5 ) . Regarding the CYP2C19 genotype , the AUC of patients with mutant alleles were higher than those of patients with wild type at a dose of 600 mg/m2 or more . The severity of toxic effects , such as myelosuppression , seemed to depend on the AUC . No partial responses were observed . One patient treated at a dose of 700 mg/m2 experienced a maximum tumor volume reduction of 22.5 % . The MTD was estimated to be 900 mg/m2 . A dose of 800 mg/m2 is recommended for further phase II studies . The pharmacokinetic/pharmacodynamic properties of E7070 seemed to be influenced by CYP2C19 genotype . The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in monotherapy or in combination chemotherapy . ( Cancer Sci 2005 ; 96 : 721 –728 Background The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer ( CRPC ) patients . Functional polymorphisms within the cytochrome P450 1B1 ( CYP1B1 ) gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen . Methods CYP1B1 genotyping was performed on blood sample s of 60 CRPC patients treated with docetaxel  , using TaqMan probes-based assays . Association between CYP1B1 - 142C > G ( leading to the 48ArgGly transition ) , 4326C > G ( 432LeuVal ) , and 4390A > G ( 453AsnSer ) polymorphisms and treatment response , progression-free-survival ( PFS ) and overall-survival ( OS ) was estimated using Pearson χ2 test , Kaplan-Meier curves and Log-rank test . Results Patients carrying the CYP1B1 - 432ValVal genotype experienced a significantly lower response-rate ( P = 0.014 ) , shorter progression-free-survival ( P = 0.032 ) and overall-survival ( P < 0.001 ) . Multivariate analyses and correction for multiple comparisons confirmed its prognostic significance for OS . No significant associations were found among other polymorphisms and both response and clinical outcome . Conclusions CYP1B1 - 4326C > G ( 432LeuVal ) polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization . Larger prospect i ve trials are warranted to vali date these findings , which might be applied to the future practice of CRPC treatment Introduction Aromatase inhibitor-associated arthralgia ( AIAA ) is a common and often debilitating symptom in breast cancer survivors . Since joint symptoms have been related to estrogen deprivation through the menopausal transition , we hypothesized that genetic polymorphisms in CYP19A1 , the final enzyme in estrogen synthesis , may be associated with the occurrence of AIAA . Methods We performed a cross-sectional study of postmenopausal women with stage 0 to III breast cancer receiving adjuvant aromatase inhibitor ( AI ) therapy .  Patient-reported AIAA was the primary outcome . DNA was genotyped for c and i date CYP19A1 polymorphisms .  Serum estrogen levels were evaluated by radioimmunoassay . Multivariate analyses were performed to examine associations between AIAA and genetic variants controlling for possible confounders . Results Among 390 Caucasian participants , 50.8 % reported AIAA . Women carrying at least one 8-repeat allele had lower odds of AIAA ( adjusted odds ratio ( AOR ) 0.41 , 95 % confidence interval ( CI ) 0.21 to 0.79 , P = 0.008 ) after adjusting for demographic and clinical covariates . Estradiol and estrone were detectable in 47 % and 86 % of subjects on AIs , respectively . Although these post-AI levels were associated with multiple genotypes , they were not associated with AIAA . In multivariate analyses , women with more recent transition into menopause ( less than five years ) were significantly more likely to report AIAA than those greater than ten years post-menopause ( AOR 3.31 , 95 % CI 1.72 to 6.39 , P < 0.001 ) . Conclusions Functional polymorphism in CYP19A1 and time since menopause are associated with patient-reported AIAA , supporting the hypothesis that the host hormonal environment contributes to the pathophysiology of AAIA . Prospect i ve investigation is needed to further delineate relationships between host genetics , changing estrogen levels and AIAA Introduction Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer . Even if most patients benefit from tamoxifen , many breast tumours either fail to respond or become resistant . Because tamoxifen is extensively metabolised by polymorphic enzymes , one proposed mechanism underlying the resistance is altered metabolism . In the present study we investigated the prognostic and /or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 ( * 3 ) , CYP2D6 ( * 4 ) , sulphotransferase 1A1 ( SULT1A1 ; * 2 ) and UDP-glucuronosyltransferase 2B15 ( UGT2B15 ; * 2 ) in tamoxifen-treated patients with breast cancer . Methods In all , 677 tamoxifen-treated postmenopausal patients with breast cancer , of whom 238 were r and omised to either 2 or 5 years of tamoxifen  , were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography . Results The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6 * 4 . For CYP3A5 , SULT1A1 and UGT2B15 no prognostic significance was observed . In the r and omised group we found that for CYP3A5 , homozygous carriers of the * 3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen , although this was not statistically significant ( hazard ratio ( HR ) = 2.84 , 95 % confidence interval ( CI ) = 0.68 to 11.99 , P = 0.15 ) . In the group r and omised to 5 years ' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival ( RFS ) among CYP3A5 * 3-homozygous patients ( HR = 0.20 , 95 % CI = 0.07 to 0.55 , P = 0.002 ) . No reliable differences could be seen between treatment duration and the genotypes of CYP2D6 , SULT1A1 or UGT2B15 . The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5 * 3 homozygotes was also seen in a multivariate Cox model ( HR = 0.13 , CI = 0.02 to 0.86 , P = 0.03 ) , whereas no differences could be seen for CYP2D6 , SULT1A1 and UGT2B15 . Conclusion The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism ; instead it is a combination of several mechanisms . However , the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy Purpose : P-glycoprotein , encoded by the mdr-1 gene , confers multidrug resistance to a variety of antineoplastic agents , e.g. , paclitaxel . Recently , different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein , as well as for the treatment response to P-glycoprotein substrates , are being clarified . We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435 T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin  in order to evaluate their predictive values . Experimental Design : Fifty-three patients were included in the study ; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months . A reference material consisting of 200 individuals was also analyzed . The genotypes of each single nucleotide polymorphism ( SNP ) were determined using Pyrosequencing . Results : The G2677T/A SNP was found to significantly correlate with treatment outcome . The probability of responding to paclitaxel treatment was higher in homozygously mutated patients ( T/T or T/A ; Fisher 's exact test ; P < 0.05 ) . The frequency of the T or A alleles was also higher in the group of patients who had a good response ( P < 0.05 ) . There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment ( χ2 test for linear-by-linear association ; P = 0.03 ) . However , the C3435 T SNP was not found to correlate to treatment outcome . Conclusions : The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy For infants and very young children with brain tumors , chemotherapy after surgical resection is the main treatment due to neurologic and neuroendocrine adverse effects from whole brain irradiation . Topotecan , an anticancer drug with antitumor activity against pediatric brain tumors , can be given intravenous or orally . However , high interpatient variability in oral drug bioavailability is common in children less than 3 years old . Therefore , this study aim ed to determine the population pharmacokinetics of  oral topotecan in infants and very young children , specifically evaluating the effects of age and ABCG2 and ABCB1 on the absorption rate constant ( Ka ) , as well as other covariate effects on all pharmacokinetic parameters . A nonlinear mixed effects model was implemented in Monolix 4.3.2 ( Lixoft , Orsay , France ) . A one-compartment model with first-order input and first-order elimination was found to adequately characterize topotecan lactone concentrations with population estimates as [ mean ( S.E. ) ] ; Ka = 0.61 ( 0.11 ) h−1 , apparent volume of distribution ( V/F ) = 40.2 ( 7.0 ) l , and apparent clearance ( CL/F ) = 40.0 ( 2.9 ) l/h . After including the body surface area in the V/F and CL/F as a power model centered on the population median , the ABCG2 rs4148157 allele was found to play a significant role in the value of Ka . Patients homozygous or heterozygous for G > A demonstrated a Ka value 2-fold higher than their GG counterparts , complemented with a 2-fold higher maximal concentration as well . These results demonstrate a possible role for the ABCG2 rs4148157 allele in the pharmacokinetics of oral topotecan in infants and very young children , and warrants further investigation Objective This study aim ed to explore the influence of SLC22A1 , PXR , ABCG2 , ABCB1 and CYP3A5 * 3 genetic polymorphisms on  imatinib mesylate ( IM ) pharmacokinetics in Asian patients with chronic myeloid leukemia ( CML ) . Patients and Methods Healthy subjects belonging to three Asian population s ( Chinese , Malay , Indian ; n = 70 each ) and CML patients ( n = 38 ) were enrolled in a prospect i ve pharmacogenetics study .  Imatinib trough ( C0h ) and clearance ( CL ) were determined in the patients at steady state . Haplowalk method was applied to infer the haplot 
    Output:
    
Nevertheless , among the investigated gene polymorphisms , it appears that the 1236C > T , 3435C > T and 2677 G > T/A SNPs of the drug transporter gene ABCB1 were the most promising determinants of clinical outcomes .
Therefore , using the haplotype ( 1236C > T , 2677G > T , and 3435C > T ) analysis rather than a single SNP may be a more useful approach for phenotype prediction .
Some of the patients with variants of CYP genes were associated with unsatisfactory treatment response ( efficacy and toxicity ) , suggesting that these variants may be associated with either reduction or absence of CYP enzyme activity .