RESUMO
BACKGROUND: The response of ovarian cancer patients to carboplatin and paclitaxel is variable, necessitating identification of biomarkers that can reliably predict drug sensitivity and resistance. In this study, we sought to identify dynamically controlled genes and pathways associated with drug response and its time dependence. METHODS: Gene expression was assessed for 14 days post-treatment with carboplatin or carboplatin-paclitaxel in xenografts from two ovarian cancer models: platinum-sensitive serous adenocarcinoma-derived OV1002 and a mixed clear cell/endometrioid carcinoma-derived HOX424 with reduced sensitivity to platinum. RESULTS: Tumour volume reduction was observed in both xenografts, but more dominantly in OV1002. Upregulated genes in OV1002 were involved in DNA repair, cell cycle and apoptosis, whereas downregulated genes were involved in oxygen-consuming metabolic processes and apoptosis control. Carboplatin-paclitaxel triggered a more comprehensive response than carboplatin only in both xenografts. In HOX424, apoptosis and cell cycle were upregulated, whereas Wnt signalling was inhibited. Genes downregulated after day 7 from both xenografts were predictive of overall survival. Overrepresented pathways were also predictive of outcome. CONCLUSIONS: Late expressed genes are prognostic in ovarian tumours in a dynamic manner. This longitudinal gene expression study further elucidates chemotherapy response in two models, stressing the importance of delayed biomarker detection and guiding optimal timing of biopsies.
Assuntos
Carboplatina/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Paclitaxel/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/genética , Ciclo Celular/genética , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Metabolismo Energético/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Ovarianas/mortalidade , Prognóstico , Via de Sinalização Wnt/genéticaRESUMO
Transforming growth factor-beta (TGF-beta) and interleukin-1 beta (IL-1 beta) have been cloned from rainbow trout (Oncorhynchus mykiss) in our laboratory. The trout TGF-beta is typical of members of the cysteine knot cytokine family, and has highest homology to TGF-beta 1, TGF-beta 4 and TGF-beta 5. The gene organisation is different to other TGF-beta genes despite the presence of seven exons. Trout IL-1 beta has less homology to known IL-1 beta s (49-56% amino acid similarity) but shows clear conservation of the secondary structure of the "mature peptide". An interleukin-converting enzyme cut site is not apparent however, and it remains to be determined whether fish IL-1 beta must be cleaved for biological activity. The trout IL-1 beta gene consists of six exons, one less than in mammals, with the missing exon at the 5' end of the gene. Two trout chemokine receptors have also been isolated in our laboratory, having high homology to CXC-R4 and CC-R7 (67% and 56% nucleotide identity respectively). With a view to studying the biological effects of fish cytokines we have also cloned the inducible nitric oxide (iNOS) and cyclooxygenase (COX-2) genes in trout. Both have high homology to known mammalian and chicken genes, and have been shown to be inducible in trout.