title: Thymidylate synthase expression determines pemetrexed targets and resistance development in tumour cells.
abstract: Although treatment options for cancer patients are increasing every year, the drug resistance problem remains very present. It is very difficult to find a drug that acts equally on tumours of the same histology as the individual's genetic characteristics often determine the response to treatment. Furthermore, tumours that initially respond to anti-tumour therapy are able to adapt and develop resistance to the drug, while others do not. In addition, this usually implies resistance development to agents to which the cells have not been exposed, a phenomenon called cross-resistance or multidrug resistance. Given this situation, it has been suggested that the most appropriate treatment would be able to act in parallel on multiple pathways constitutively altered in tumour cells. Pemetrexed is a multitargeted antifolate that exerts its activity against folate-dependent enzymes involved in de novo pyrimidine and purine synthesis. It is currently in use in combination with cisplatin against malignant pleural mesothelioma and non-squamous non-small cell lung cancer with favourable results. By real-time RT-PCR gene expression assays and restoration viability assays we demonstrated that Pemetrexed targets folate-dependent enzymes involved in de novo biosynthesis of purines differently depending on the intrinsic genetic characteristics of the tumour. These differences did not, however, interfere either with the initial response to the drug or with the activation of apoptotic pathways. In addition, these genetic fingerprints can differentiate two groups of tumours: those capable of developing resistance to antifolate, and not capable. These results may be useful to employ targets gene expression as resistance markers, a valuable tool for identifying patients likely to receive combination therapy to prevent the development of resistance.
authors.affiliation: Medical Oncology Research Laboratory, Cruces Universtity Hospital, Bizkaia, Spain. aitziber.buquemartinez@osakidetza.net
authors.forename: Aitziber
authors.initials: A
authors.lastname: Buqué
authors.forename: Unai
authors.initials: U
authors.lastname: Aresti
authors.forename: Begoña
authors.initials: B
authors.lastname: Calvo
authors.forename: Jangi
authors.initials: J
authors.lastname: Sh Muhialdin
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Sergio
authors.initials: S
authors.lastname: Carrera
authors.forename: Eider
authors.initials: E
authors.lastname: Azkona
authors.forename: Itziar
authors.initials: I
authors.lastname: Rubio
authors.forename: Guillermo
authors.initials: G
authors.lastname: López-Vivanco
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D009928:Organ Specificity; D000068437:Pemetrexed; D011687:Purines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; D011687:Purines; D011743:Pyrimidines; D000068437:Pemetrexed; D006147:Guanine; D013940:Thymidylate Synthase; D002945:Cisplatin