生物谷報(bào)道： St. Jude兒童研究醫(yī)院研究人員最近發(fā)現(xiàn)，irinotecan治療不需進(jìn)行昂貴的基因預(yù)測(cè)試（檢測(cè)藥物是否對(duì)患者有副作用）環(huán)節(jié),，且多次低劑量注射治癌藥物irinotecan比一次性大量注射有效,。
irinotecan常用于治療兒童實(shí)體腫瘤如成神經(jīng)細(xì)胞瘤、肉瘤和腎瘤,。人體中的UGTIA1酶能夠催化irinotecan的活性形式——SN-38，便于細(xì)胞很快清除SN-38,，但UGTIA1酶的UGT1A1*28的形式不能催化SN-38，結(jié)果聚集在體內(nèi)的SN-38引發(fā)腹瀉或neutropenia,。Neutropenia（嗜中性白血球減少癥）患者免疫力差，體內(nèi)的嗜中性粒細(xì)胞（免疫細(xì)胞）數(shù)量明顯偏低,。
UGT1A1基因的啟動(dòng)子區(qū)有6個(gè)TA,，而UGT1A1*28的啟動(dòng)子區(qū)有7個(gè)TA。之前的研究結(jié)果顯示,，攜帶兩個(gè)UGT1A1*28基因的成年人接受一次高劑量irinotecan注射后,，出現(xiàn)嚴(yán)重腹瀉或neutropenia,。美國(guó)食品和藥品監(jiān)督管理局要求irinotecan的包裝上注明該藥容易使UGT1A1*28基因純合子患者產(chǎn)生neutropenia,，并且叮囑臨床醫(yī)師慎重考慮給藥劑量。
文章第一作者Clinton Stewart想知道,，連續(xù)兩周對(duì)帶有兩個(gè)UGT1A1*28基因拷貝的兒童注射低劑量（正常水平的1/10）irinotecan是否會(huì)引起腹瀉或neutropenia。
接受低劑量注射治療的74名實(shí)體腫瘤兒童患者中,，27名有兩個(gè)正常UGT1A1基因拷貝,，36名既有UGT1A1*28基因又有UGT1A1正常基因,，9名有兩個(gè)UGT1A1*28基因拷貝。結(jié)果顯示,，UGT1A1*28基因與腹瀉、neutropenia之間沒(méi)有相關(guān)性,。因此，研究人員認(rèn)為檢測(cè)患者是否有UGT1A1*28基因是沒(méi)有實(shí)際用途的,。
研究結(jié)果提示：臨床醫(yī)師不必檢測(cè)兒童是否攜帶與neutropenia副作用相關(guān)的UGT1A1基因突變,，直接進(jìn)行irinotecan治療,，并且兩周內(nèi)低劑量給藥取代標(biāo)準(zhǔn)的每月一次的大量給藥,，irinotecan能夠很快發(fā)揮藥效。研究結(jié)果刊登于6月20日J(rèn)ournal of Clinical Oncology,。
文章高級(jí)作者Lisa McGregor說(shuō),，這項(xiàng)發(fā)現(xiàn)有助于臨床醫(yī)師設(shè)計(jì)有效、安全的irinotecan治療措施,。
原始出處:
Journal of Clinical Oncology, Vol 25, No 18 (June 20), 2007: pp. 2594-2600
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.10.2301
UGT1A1 Promoter Genotype Correlates With SN-38 Pharmacokinetics, but Not Severe Toxicity in Patients Receiving Low-Dose Irinotecan
Clinton F. Stewart, John C. Panetta, Melinda A. O'Shaughnessy, Stacy L. Throm, Charles H. Fraga, Thandranese Owens, Tiebin Liu, Catherine Billups, Carlos Rodriguez-Galindo, Amar Gajjar, Wayne L. Furman, Lisa M. McGregor
From the Departments of Pharmaceutical Sciences, Oncology, and Biostatistics, St Jude Children's Research Hospital, Memphis, TN
Address reprint requests to Clinton F. Stewart, PharmD, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 North Lauderdale, Mail Stop 313, Memphis, TN 38105; e-mail: [email protected]
Purpose: To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks).
Patients and Methods: Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy.
Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios.
Conclusion: Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.
Supported by US Public Health Service Childhood Solid Tumor Program Grant No. CA23099, Cancer Center Support (CORE) Grant No. CA21765, and by American Lebanese Syrian Associated Charities. AstraZeneca Pharmaceuticals provided support for the conduct of the gefitinib clinical trial.
Preliminary data were presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
