Zusammenfassung
Gen-Polymorphismen haben Einfluss auf die Effektivität eines Wirkstoffes, wenn sie
in Genen lokalisiert sind, deren Enzyme am Stoffwechsel eines Medikamentes beteiligt
sind. Etwa 40 % aller Wirkstoffe werden durch die genetisch polymorphe Enzymfamilie
P450 Cytochrom metabolisiert, die den therapeutischen Erfolg modifizieren können.
Ziel der pharmakogenetischen Analyse ist die frühzeitige Erkennung und Vermeidung
von genetisch bedingten Medikamentennebenwirkungen sowie eine therapiebedingte Dosisanpassung.
Für einige onkologisch wirksame Medikamente werden Polymorphismen beschrieben, deren
Kenntnis helfen kann, die Ansprechrate in der onkologischen Therapie zu verbessern.
Summary
Genes of drug metabolizing enzymes modulate the efficacy of drugs if their polymorphisms
contribute to an altered enzyme activity. Approximately 40 % of all drugs are metabolized
by enzymes of the polymorphic P450 cytochrome family. This may lead to a modified
therapeutical success due to gene variants which also affects cytostatic treatments.
The aim of pharmacogenetic diagnostics is the detection of these polymorphisms before
starting treatment. These informations are helpful to reduce the number of adverse
drug reactions and allow dose adjustment according to the genotype. The introduction
of molecular devices into therapies may also optimize the response to cytostatic treatments.
Schlüsselwörter
Polymorphismen - Medikamentenstoffwechsel - individuelle Variabilität - TPMT - UGT1A1
- EGFR - P450 Cytochrom
Keywords
Polymorphisms - drug metabolism - individual varability - TPMT - UGT1A1 - EGFR - P450
cytochrome
Literatur
- 01
Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K,
Hasegawa Y.
Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic
analysis.
Cancer Res.
2000;
60
(24)
6921-6
- 02
Beutler E, Gelbart T, Demina A.
Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced
polymorphism for regulation of bilirubin metabolism?.
Proc Natl Acad Sci USA.
1998;
95
(14)
8170-4
- 03
Bratherton D G, Brown C H, Buchanan R, Hall V, Kingsley Pillers E M, Wheeler T K,
Williams C J.
A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced
breast cancer: 10 mg bd versus 20 mg bd.
Br J Cancer.
1984;
50
(2)
199-205
- 04
Chou W H, Yan F X, Leon J de, Barnhill J, Rogers T, Cronin M, Pho M, Xiao V, Ryder T B,
Liu W W, Teiling C, Wedlund P J.
Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome
and costs associated with severe mental illness.
J Clin Psychopharmacol.
2000;
20
(2)
246-51
- 05
Evans W E, Hon Y H, Bomgaars L, Coutre S, Holdsworth M, Janco R, Kalwinsky D, Keller F,
Khatib Z, Margolin J, Murray J, Quinn J, Ravindranath Y, Ritchey K, Roberts W, Rogers Z R,
Schiff D, Steuber C, Tucci F, Kornegay N, Krynetski E Y, Relling M V.
Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among
patients intolerant to mercaptopurine or azathioprine.
J Clin Oncol.
2001;
19
(8)
2293-301
- 06
Font A, Sanchez J M, Taron M, Martinez-Balibrea E, Sanchez J J, Manzano J L, Margeli M,
Richardet M, Barnadas A, Abad A, Rosell R.
Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer
patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)
polymorphism.
Invest New Drugs.
2003;
21
(4)
435-43
- 07
Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard J Y, Nishiwaki Y, Vansteenkiste J,
Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A,
Feyereislova A, Dong R P, Baselga J.
Multi-institutional randomized phase II trial of gefitinib for previously treated
patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].
J Clin Oncol.
2003;
21
(12)
2237-46
- 08
Goetz M P, Rae J M, Suman V J, Safgren S L, Ames M M, Visscher D W, Reynolds C, Couch F J,
Lingle W L, Flockhart D A, Desta Z, Perez E A, Ingle J N.
Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes
of efficacy and hot flashes.
J Clin Oncol.
2005;
23
(36)
9312-8
- 09
Innocenti F, Undevia S D, Iyer L, Chen P X, Das S, Kocherginsky M, Karrison T, Janisch L,
Ramirez J, Rudin C M, Vokes E E, Ratain M J.
Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe
neutropenia of irinotecan.
J Clin Oncol.
2004;
22
(8)
1382-8
- 10
Ishikawa K, Kajita Y, Hasegawa Y, Noda Y, Yoshida J, Nabeshima T.
Irinotecan therapy in a 12-year-old girl with recurrent brain stem glioma and without
functional polymorphisms in UGT1A1 activity: case report.
J Neurooncol.
2005;
74
(3)
283-6
- 11
Iyer L, King C D, Whitington P F, Green M D, Roy S K, Tephly T R, Coffman B L, Ratain M J.
Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate
glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite
(SN-38) in human liver microsomes.
J Clin Invest.
1998;
101
(4)
847-54
- 12
Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee K H, Skaar T, Storniolo A M, Li L, Araba A,
Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum R M, Rae J M, Hayes D F,
Flockhart D A.
CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast
cancer treatment.
J Natl Cancer Inst.
2005;
97
(1)
30-9
- 13
Jordan V C, Collins M M, Rowsby L, Prestwich G.
A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity.
J Endocrinol.
1977;
75
(2)
305-16
- 14
Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K.
Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11,
in the antitumor effect of CPT-11.
Cancer Res.
1991;
51
(16)
4187-91
- 15
Kirchheiner J, Nickchen K, Bauer M, Wong M L, Licinio J, Roots I, Brockmöller J.
Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic
variations to the phenotype of drug response.
Mol Psychiatry.
2004;
9
(5)
442-73
- 16
Lennard L, Lilleyman J S, van Loon J, Weinshilboum R M.
Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic
leukaemia.
Lancet.
1990;
336
(8709)
225-9
- 17
Lennard L, Loon J A van, Lilleyman J S, Weinshilboum R M.
Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase
activity and 6-thioguanine nucleotide concentrations.
Clin Pharmacol Ther.
1987;
41
(1)
18-25
- 18
Lynch T J, Bell D W, Sordella R, Gurubhagavatula S, Okimoto R A, Brannigan B W, Harris P L,
Haserlat S M, Supko J G, Haluska F G, Louis D N, Christiani D C, Settleman J, Habery D A.
Activating mutations in the epidermal growth factor receptor underlying responsiveness
of non-small-cell lung cancer to gefitinib.
N Engl J Med.
2004;
350
(21)
2129-39
- 19
McLeod H L, Krynetski E Y, Relling M V, Evans W E.
Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for
childhood acute lymphoblastic leukemia.
Leukemia.
2000;
14
(4)
567-72
- 20
Paez J G, Janne P A, Lee J C, Tracy S, Greulich H, G abriel S, Herman P, Kaye F J,
Lindeman N, Boggon T J, Naoki K, Sasaki H, Fujii Y, Eck M J, Sellers W R, Johnson B E,
Meyerson M.
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
Science.
2004;
304
(5676)
1497-500
- 21
Relling M V, Hancock M L, Boyett J M, Pui C H, Evans W E.
Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia.
Blood.
1999;
93
(9)
2817-23
- 22
Rothenberg M L, Eckardt J R, Kuhn J G, Burris 3rd H A, Nelson J, Hilsenbeck S G, Rodriguez G I,
Thurman A M, Smith L S, Eckardt S G, Weiss G R, Elfring G L, Rinaldi D A, Schaaf L J,
Hoff D D von.
Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal
cancer.
J Clin Oncol.
1996;
14
(4)
1128-35
- 23
Rouits E, Boisdron-Celle M, Dumont A, Guerin O, Morel A, Gamelin E.
Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular
and clinical study of 75 patients.
Clin Cancer Res.
2004;
10
(15)
5151-9
- 24
Salavaggione O E, Wang L, Wiepert M, Yee V C, Weinshilboum R M.
Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative
genomics.
Pharmacogenet Genomics.
2005;
15
(11)
801-15
- 25
Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, Zanger U M,
Schwab M.
Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation
in a large population of German-Caucasians and identification of novel TPMT variants.
Pharmacogenetics.
2004;
14
(7)
407-17
- 26
Schutz E, Gummert J, Mohr F, Oellerich M.
Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart
transplant recipient.
Lancet.
1993;
341
(8842)
436
- 27
Stanulla M, Schaeffeler E, Flohr T, Cario G, Schrauder A, Zimmermann M, Welte K, Ludwig W D,
Bartram C R, Zanger U M, Eichelbaum M, Schrappe M, Schwab M.
Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine
in childhood acute lymphoblastic leukemia.
JAMA.
2005;
293
(12)
1485-9
- 28
Wasserman E, Myara A, Lokiec F, Goldwasser F, Trivin F, Mahjoubi M, Misset J L, Cvitkovic E.
Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports.
Ann Oncol.
1997;
8
(10)
1049-51
- 29
Weinshilboum R M, Sladek S L.
Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase
activity.
Am J Hum Genet.
1980;
32
(5)
651-62
- 30
Yates C R, Krynetski E Y, Loennechen T, Fessing M Y, Tai H L, Pui C H, Relling M V,
Evans W E.
Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for
azathioprine and mercaptopurine intolerance.
Ann Intern Med.
1997;
126
(8)
608-14
Korrespondenzadresse
Dr. med. Eckart Schnakenberg
Institut für Pharmakogenetik und
Genetische Disposition (IPGD)
Ostpassage 7
30853 Langenhagen
Email: es@ipgd.org
