Determinants of chemosensitivity in gastric cancer.
Recent advances in the management of gastric cancer, especially in the arena of chemotherapy, are paving the way for optimization of treatment that maximizes effectiveness while minimizing toxicity. The expansion of the chemotherapeutic armamentarium has led to multiple combinations of cytotoxic agents. Unfortunately, the benefit of chemotherapy has been modest at best, and no one combination has shown significant superiority over the others in comparative Phase III trials. It is in this setting that pharmacogenetic advances have the potential to play an important role in achieving superior clinical outcome among different subsets of patients through prospective prediction of clinical benefit to particular regimens. We are just beginning to make inroads in gastric cancer pharmacogenetics, mostly through small, pilot retrospective studies. Several potential candidates, such as thymidylate synthase, excision repair complementation group 1 and glutahione S-transferase P1, have been identified so far and more are bound to surface, especially when biologic therapies are added to the armamentarium. Serious challenges lay ahead given the complex nature of cytotoxic metabolism with multiple players working together to influence drug effectiveness and/or toxicity. Well-designed large prospective trials are needed to identify key genes among the multiple potential candidates that can help a clinician make real-time treatment decisions in respect to a particular regimen depending on a patient's pharmacogenetic profile.
Park
David J
DJ
Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.
Lenz
Heinz-Josef
HJ
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000378:metabolism; D005472:Fluorouracil / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009154:Mutation; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000627:therapeutic use; D013940:Thymidylate Synthase / Q000378:metabolism; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000378:metabolism; D000099148:UGT1A1 Enzyme
D000970:Antineoplastic Agents; D002166:Camptothecin; D004268:DNA-Binding Proteins; D042943:Dihydrouracil Dehydrogenase (NADP); D004720:Endonucleases; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D051549:Glutathione S-Transferase pi; D000077146:Irinotecan; D009944:Organoplatinum Compounds; D043823:Taxoids; D013940:Thymidylate Synthase; D051759:Xeroderma Pigmentosum Group D Protein; D000099148:UGT1A1 Enzyme; C496556:GSTP1 protein, human; C071447:ERCC1 protein, human; C497292:ERCC2 protein, human