Relationship between antimetabolite toxicity and pharmacogenetics in Turkish cancer patients.
BACKGROUND
Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration.


METHODS
Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5' UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms.


RESULTS
Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population.


CONCLUSIONS
Pharmacogenetics might contribute to tailored therapy.
Dept of Medical Oncology, School of Medicine, Ankara University, Ankara, Turkey. mutludogan1@yahoo.com
Mutlu
M
Dogan
Halil G
HG
Karabulut
Ajlan
A
Tukun
Ahmet
A
Demirkazik
Gungor
G
Utkan
Bulent
B
Yalcin
Dilek
D
Dincol
Hakan
H
Akbulut
Fikri
F
Icli
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001859:Bone Neoplasms / Q000188:drug therapy*; D001943:Breast Neoplasms / Q000188:drug therapy*; D000069287:Capecitabine; D004247:DNA / Q000032:analysis / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D003875:Drug Eruptions / Q000209:etiology; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D018598:Minisatellite Repeats; D052016:Mucositis / Q000139:chemically induced; D012516:Osteosarcoma / Q000188:drug therapy*; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics; D014421:Turkey; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D003841:Deoxycytidine; D000069287:Capecitabine; D004247:DNA; D042943:Dihydrouracil Dehydrogenase (NADP); C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D000410:Alanine Transaminase; D051759:Xeroderma Pigmentosum Group D Protein; D005472:Fluorouracil; D008727:Methotrexate