RESUMEN
The current convergence of molecular and pharmacological data provides unprecedented opportunities to gain insights into the relationships between the two types of data. Multiple forms of large-scale molecular data, including but not limited to gene and microRNA transcript expression, DNA somatic and germline variations from next-generation DNA and RNA sequencing, and DNA copy number from array comparative genomic hybridization are all potentially informative when one attempts to recognize the panoply of potentially influential events both for cancer progression and therapeutic outcome. Concurrently, there has also been a substantial expansion of the pharmacological data being accrued in a systematic fashion. For cancer cell lines, the National Cancer Institute cell line panel (NCI-60), the Cancer Cell Line Encyclopedia (CCLE), and the collaborative Genomics of Drug Sensitivity in Cancer (GDSC) databases all provide subsets of these forms of data. For the patient-derived data, The Cancer Genome Atlas (TCGA) provides analogous forms of genomic information along with treatment histories. Integration of these data in turn relies on the fields of statistics and statistical learning. Multiple algorithmic approaches may be chosen, depending on the data being considered, and the nature of the question being asked. Combining these algorithms with prior biological knowledge, the results of molecular biological studies, and the consideration of genes as pathways or functional groups provides both the challenge and the potential of the field. The ultimate goal is to provide a paradigm shift in the way that drugs are selected to provide a more targeted and efficacious outcome for the patient.
Asunto(s)
Algoritmos , Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Farmacogenética , Humanos , Medicina de PrecisiónRESUMEN
5-Fluorouracil (5-FU) is an antineoplasic drug widely used to treat cancer. Its cytotoxic effect has been principally ascribed to the misincorporation of fluoronucleotides into DNA and RNA during their synthesis, and the inhibition of thymidylate synthase (TS) by FdUMP (one of the 5-FU active metabolites), which leads to nucleotide pool imbalance. In the present study, we compared the ability of 5-FU and FdUMP to induce apoptosis and to influence the cell cycle progression in human colon SW620 adenocarcinoma cells in regards to their genotoxic and clastogenic activities. Our study demonstrates that 5-FU induces SSB, DSB and apoptosis earlier than FdUMP. Interestingly, while both drugs are able to induce apoptosis, their effect on the cell cycle progression differed. Indeed, 5-FU induces an arrest in G1/S while FdUMP causes an arrest in G2/M. Independently of the temporal difference in strand breaks and apoptosis induction, as well as the differential cell cycle modulation, both drugs presented similar clastogenic effects. The different pattern of cell cycle arrest suggests that the two drugs induce different types of primary DNA lesions that could lead to the activation of different checkpoints and recruit different DNA repair pathways.
Asunto(s)
Antimetabolitos Antineoplásicos/toxicidad , ADN de Neoplasias/efectos de los fármacos , Fluorodesoxiuridilato/toxicidad , Fluorouracilo/toxicidad , Antimetabolitos Antineoplásicos/química , Antimetabolitos Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Daño del ADN , Fluorodesoxiuridilato/química , Fluorodesoxiuridilato/farmacocinética , Fluorouracilo/química , Fluorouracilo/farmacocinética , Histonas/genética , Humanos , Pruebas de Micronúcleos , Mutágenos/toxicidadRESUMEN
The analgesic drug dipyrone is used to treat side effects (including pain and fever) of cancer chemotherapeutic agents. Dipyrone is metabolized to 4-aminoantipyrine (4-AA), a PGE2-dependent blocker and inhibitor of cyclooxygenase (COX). We evaluated the genotoxic, mutagenic, apoptotic, and immunomodulatory activities of 4-AA in vivo and the effects of its combination with the antineoplastic drugs doxorubicin, cisplatin, and cyclophosphamide. 4-AA did not cause genotoxic/mutagenic damage, splenic phagocytosis, or leukocyte alterations. However, when combined with the antineoplastic agents, 4-AA decreased their genotoxic, mutagenic, apoptotic, and phagocytic effects. These results suggest that 4-AA might interfere with DNA damage-mediated chemotherapy.
Asunto(s)
Ampirona/farmacología , Cisplatino/toxicidad , Ciclofosfamida/toxicidad , Doxorrubicina/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Ensayo Cometa , Daño del ADN/efectos de los fármacos , Masculino , Ratones , Pruebas de Micronúcleos , Fagocitosis/efectos de los fármacosRESUMEN
5-Fluorouracil (5-FU) is an antitumor antimetabolite that can be converted into fluoronucleotides and FdUMP. Fluoronucleotides are incorporated into DNA and RNA, while FdUMP results in nucleotide pool imbalance. Saccharomyces cerevisiae is unable to convert 5-FU into FdUMP, making yeast a unique model system to study the cellular effects of 5-FU and FdUMP independently. A panel of repair-deficient yeast strains was used to identify the DNA repair pathways needed for repair of lesions generated by 5-FU or FdUMP. This included yeast deficient in base excision repair (BER), nucleotide excision repair (NER), translesion synthesis (TLS), mismatch repair (MMR), post-replication repair (PRR), homologous recombination (HR) and non-homologous end-joining (NHEJ). The results revealed an important role of BER, since BER-mutants (ntg1, ntg2, apn1, apn2) showed pronounced sensitivity to both 5-FU and FdUMP. MMR mutants also showed high sensitivity to both compounds. In contrast, deficiencies in NER, NHEJ and TLS repair had only minor influence on the sensitivity to FU and FdUMP. Interestingly, deficiencies in HR (rad52) and PPR (rad6, rad18) were associated with increased sensitivity to 5-FU, but not to FdUMP. Taken together, our study reveals an important contribution of DNA repair pathways on the sensitivity to 5-FU and its active metabolite FdUMP. Importantly, the repair mechanisms differed for the 2 antimetabolites since lesions induced by 5-FU were repaired by BER, MMR, HR and PRR, while only BER and MMR were required for repair of FdUMP-induced lesions.