RESUMO
Therapeutic outcomes of combination chemotherapy have not significantly advanced during the past decades. This has been attributed to the formidable challenges of optimizing drug combinations. Testing a matrix of all possible combinations of doses and agents in a single cell line is unfeasible due to the virtually infinite number of possibilities. We utilized the Feedback System Control (FSC) platform, a phenotype oriented approach to test 100 options among 15,625 possible combinations in four rounds of assaying to identify an optimal tri-drug combination in eight distinct chemoresistant bladder cancer cell lines. This combination killed between 82.86% and 99.52% of BCa cells, but only 47.47% of the immortalized benign bladder epithelial cells. Preclinical in vivo verification revealed its markedly enhanced anti-tumor efficacy as compared to its bi- or mono-drug components in cell line-derived tumor xenografts. The collective response of these pathways to component drugs was both cell type- and drug type specific. However, the entire spectrum of pathways triggered by the tri-drug regimen was similar in all four cancer cell lines, explaining its broad spectrum killing of BCa lines, which did not occur with its component drugs. Our findings here suggest that the FSC platform holds promise for optimization of anti-cancer combination chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Modelos Teóricos , Neoplasias da Bexiga Urinária/metabolismo , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: The polymorphism of p53 codon 72 (Arg72Pro) has been suggested to play an important role in many cancers and may influence the response to chemotherapy. Our aim was to investigate the association of p53 Arg72Pro polymorphism with the clinical outcome of gastric cancer patients treated with 5-FU-based adjuvant chemotherapy. METHODS: The p53 codon 72 genotype was determined in blood samples from 110 Chinese patients with gastric cancer treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy, using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. RESULTS: Kaplan-Meier survival analysis showed that gastric cancer patients with Pro/Pro genotype had shorter relapse-free survival (chi(2) = 10.632, P = 0.005) and overall survival (chi(2) = 7.104, P = 0.029) than patients with other genotypes. Cox multivariate analysis showed that Pro/Pro genotype was associated with statistically significant reduced relapse-free survival (adjusted OR = 3.049, 95% CI: 1.363-6.819, P = 0.007) and overall survival (adjusted OR = 2.581, 95% CI: 1.052-6.330, P = 0.038). CONCLUSION: These results suggested that p53 codon 72 polymorphism appears to be an independent prognostic factor in gastric cancer patients treated with 5-FU-based adjuvant chemotherapy.