Pharmacogenetics of extraordinary responses to 5-FU/cisplatin chemotherapy in advanced gastric cancer -- report of 2 cases.
BACKGROUND
Gastric cancer is often diagnosed in the metastatic stage, and only 10% of patients survive for as long as 2 years. Current chemotherapy regimens show significant treatment-related toxicities. It is crucial to identify the patients that will benefit most from certain chemotherapy regimens in order to avoid unnecessary side effects.


METHODS
2 patients with advanced gastric cancer repeatedly received 5-FU/cisplatin combination chemotherapy. Genomic DNA was extracted from tumor tissue and mononuclear blood cells. Genotype analysis of genes of metabolizing and DNA repair enzymes was carried out using a PCR-RFLP technique. Direct sequencing was used to identify mutations of the gene dihydropyrimidine dehydrogenase (DPD).


RESULTS
Prolonged survival of 51 and 29 months, respectively were observed in our 2 patients. Both patients were positive for genotypes of thymidylate synthase -- the target enzyme of 5-FU -- that are associated with improved drug response. DPD variants connected with increased toxicity were not observed. However, both patients also showed genotypes in cisplatin metabolizing enzymes which enhance the effect of the drug.


CONCLUSIONS
Genotype analysis in drug metabolizing enzymes of 5-FU and cisplatin provide a possible explanation for extraordinary therapy effects observed in 2 patients with advanced gastric cancer.
Wolschke
Christine
C
Medizinische Klinik II, Onkologie, Hämatologie und Knochenmarkstransplantation, Universitätsklinikum Hamburg-Eppendorf, Germany.
Goekkurt
Eray
E
Al-Batran
Salah-Eddin
SE
Hossfeld
Dieter Kurt
DK
Stoehlmacher
Jan
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011379:Prognosis; D012720:Severity of Illness Index; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
D013940:Thymidylate Synthase; D002945:Cisplatin; D005472:Fluorouracil