40 results on '"Trejo-Becerril, C."'
Search Results
2. Hereditary diffuse gastric cancer (HDGC). An overview
- Author
-
Taja-Chayeb, L, Vidal-Millán, S, Trejo-Becerril, C, Pérez-Cárdenas, E, Chávez-Blanco, A, Domínguez-Gómez, G, González-Fierro, A, Romo-Pérez, A, and Dueñas-González, A
- Published
- 2022
- Full Text
- View/download PDF
3. Pharmacogenetics and pharmacoepigenetics of gemcitabine
- Author
-
Candelaria, M., de la Cruz-Hernández, E., Pérez-Cárdenas, E., Trejo-Becerril, C., Gutiérrez-Hernández, O., and Dueñas-González, A.
- Published
- 2010
- Full Text
- View/download PDF
4. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors
- Author
-
Candelaria, M., Gallardo-Rincón, D., Arce, C., Cetina, L., Aguilar-Ponce, J.L., Arrieta, Ó, González-Fierro, A., Chávez-Blanco, A., de la Cruz-Hernández, E., Camargo, M.F., Trejo-Becerril, C., Pérez-Cárdenas, E., Pérez-Plasencia, C., Taja-Chayeb, L., Wegman-Ostrosky, T., Revilla-Vazquez, A., and Dueñas-González, A.
- Published
- 2007
- Full Text
- View/download PDF
5. Pharmacokinetics of hydralazine, an antihypertensive and DNA-demethylating agent, using controlled-release formulations designed for use in dosing schedules based on the acetylator phenotype
- Author
-
Gonzalez-Fierro, A., primary, Vasquez-Bahena, D., additional, Taja-Chayeb, L., additional, Vidal, S., additional, Trejo-Becerril, C., additional, Pérez-Cardenas, E., additional, Cruz-Hernández, E. de la, additional, Chávez-Blanco, A., additional, Gutiérrez, O., additional, Rodriguez, D., additional, Fernandez, Z., additional, and Duenas-González, A., additional
- Published
- 2011
- Full Text
- View/download PDF
6. Epigenetic changes in nucleoside transporter hENT1 and dCK, as mechanism for gemcitabine-aquired resistance in cervical cancer cell lines.
- Author
-
Candelaria, M., primary, de la Cruz-Hernandez, E., additional, Gonzalez-Fierro, A., additional, Perez-Cardenas, E., additional, Trejo-Becerril, C., additional, Taja-Chayeb, L., additional, and Duenas- Gonzalez, A., additional
- Published
- 2010
- Full Text
- View/download PDF
7. Pharmacogenetics and pharmacoepigenetics of gemcitabine
- Author
-
Candelaria, M., primary, de la Cruz-Hernández, E., additional, Pérez-Cárdenas, E., additional, Trejo-Becerril, C., additional, Gutiérrez-Hernández, O., additional, and Dueñas-González, A., additional
- Published
- 2009
- Full Text
- View/download PDF
8. A phase II trial of epigenetic therapy with hydralazine and magnesium valproate associated to doxorubicin and cyclophosphamide for locally advanced breast cancer
- Author
-
Arce-Salinas, C., primary, Segura-Pacheco, B., additional, Vela-Chavez, T., additional, Bargallo-Rocha, E., additional, Pérez-Cárdenas, E., additional, Taja-Chayeb, L., additional, Trejo-Becerril, C., additional, Revilla-Vazquez, A., additional, and Dueñas-González, A., additional
- Published
- 2006
- Full Text
- View/download PDF
9. Neuroendocrine Marker Expression in Cervical Carcinomas of Non-Small Cell Type
- Author
-
Chavez-Blanco, A., primary, Taja-Chayeb, L., additional, Cetina, L., additional, Chanona-Vilchis, G., additional, Trejo-Becerril, C., additional, Perez-Cardenas, E., additional, Segura-Pacheco, B., additional, Acu??a-Gonz??lez, C., additional, and Due??as-Gonzalez, A., additional
- Published
- 2002
- Full Text
- View/download PDF
10. Epigenetic therapy and cisplatin chemoradiation in FIGO Stage IIIB cervical cancer.
- Author
-
Candelaria, M., Cetina, L., Pérez-Cárdenas, E., de la Cruz-Hernández, E., González-Fierro, A., Trejo-Becerril, C., Taja-Chayeb, L., Chanona, J., Arias, D., and Dueñas-González, A.
- Abstract
The article presents a study which evaluates the safety and efficacy of epigenetic therapy and cisplatin chemoradiation in International Federation of Gynecology and Obstetrics (FIGO) Stage IIIB cervical cancer patients. The study uses high-performance liquid chromatographic (HPLC) to determine hydralazine in plasma and fluorescence polarization immunoassay technology to measure valproic acid. It shows that hydralazine and valproic acid are safe when administered with cisplatin chemoradiation.
- Published
- 2010
11. Immunohistochemical expression of p53 in breast carcinoma is associated with the intron 1 BglII polymorphism of the p53 gene
- Author
-
Trejo-Becerril, C., Sarmiento, R. G., Abad, M. M., Ichaso, N., Delgado, R., Cruz, J. J., and Duenas-Gonzalez, A.
- Published
- 2000
- Full Text
- View/download PDF
12. Identification of peptides presented by HLA class I molecules on cervical cancer cells with HPV-18 infection
- Author
-
Monroy-Garca, A., Ortz-Navarrete, V.F., Mora-Garca, M.d.L., Flores-Borja, F., Diaz-Quinonez, A., Isibasi-Araujo, A., Trejo-Becerril, C., Chacon-Salinas, R., Hernandez-Montes, J., and Granados-Arreola, J.
- Published
- 1999
- Full Text
- View/download PDF
13. The role of extracellular DNA (exDNA) in cellular processes.
- Author
-
Fernández-Domínguez IJ, Manzo-Merino J, Taja-Chayeb L, Dueñas-González A, Pérez-Cárdenas E, and Trejo-Becerril C
- Subjects
- Humans, Prognosis, DNA genetics, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Nowadays, extracellular DNA or circulating cell-free DNA is considered to be a molecule with clinical applications (diagnosis, prognosis, monitoring of treatment responses, or patient follow-up) in diverse pathologies, especially in cancer. Nevertheless, because of its molecular characteristics, it can have many other functions. This review focuses on the participation of extracellular DNA (exDNA) in fundamental processes such as cell signaling, coagulation, immunity, evolution through horizontal transfer of genetic information, and adaptive response to inflammatory processes. A deeper understanding of its role in each of these processes will allow development of better tools to monitor and control pathologies, as well as helping to generate new therapeutic options, beyond the applicability of DNA in liquid biopsy.
- Published
- 2021
- Full Text
- View/download PDF
14. Antimetastatic effect of epigenetic drugs, hydralazine and valproic acid, in Ras-transformed NIH 3T3 cells.
- Author
-
Pérez-Cárdenas E, Taja-Chayeb L, Trejo-Becerril C, Chanona-Vilchis J, Chávez-Blanco A, Domínguez-Gómez G, Langley E, García-Carrancá A, and Dueñas-González A
- Abstract
Introduction: Metastasis involves the accumulation of genetic and epigenetic alterations leading to activation of prometastatic genes and inactivation of antimetastatic genes. Among epigenetic alterations, DNA hypermethylation and histone hypoacetylation are the focus of intense translational research because their pharmacological inhibition has been shown to produce antineoplastic activity in a variety of experimental models., Aims: This study aimed to evaluate the antimetastatic effect of the DNA-methylation inhibitor, hydralazine, and the histone deacetylase inhibitor, valproic acid., Methods: NIH 3T3- Ras murine cells were treated with hydralazine and valproic acid to evaluate their effects upon cell proliferation, cell motility, chemotaxis, gelatinase activity, and gene expression. Lung metastases were developed by intravenous injection of NIH 3T3- Ras cells in BALB/c nu/nu mice and then treated with the drug combination., Results: Treatment induced a growth-inhibitory effect on NIH 3T3- Ras cells, showed a trend toward increased gelatinase activity of MMP2 and MMP9, and inhibited chemotaxis and cell motility. The combination led to a strong antimetastatic effect in lungs of nude mice., Conclusion: Hydralazine and valproic acid, two repositioned drugs as epigenetic agents, exhibit antimetastatic effects in vitro and in vivo and hold potential for cancer treatment., Competing Interests: Disclosure The authors report no conflicts of interest in this work.
- Published
- 2018
- Full Text
- View/download PDF
15. Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy.
- Author
-
Schcolnik-Cabrera A, Chávez-Blanco A, Domínguez-Gómez G, Taja-Chayeb L, Morales-Barcenas R, Trejo-Becerril C, Perez-Cardenas E, Gonzalez-Fierro A, and Dueñas-González A
- Subjects
- Administration, Intravenous, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Drug Design, Drug Repositioning, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Humans, Lactones administration & dosage, Lactones pharmacology, Molecular Targeted Therapy, Neoplasms enzymology, Neoplasms pathology, Orlistat, Fatty Acid Synthase, Type I antagonists & inhibitors, Lactones therapeutic use, Neoplasms drug therapy
- Abstract
Introduction: Cancer cells have increased glycolysis and glutaminolysis. Their third feature is increased de novo lipogenesis. As such, fatty acid (FA) synthesis enzymes are over-expressed in cancer and their depletion causes antitumor effects. As fatty acid synthase (FASN) plays a pivotal role in this process, it is an attractive target for cancer therapy., Areas Covered: This is a review of the lipogenic phenotype of cancer and how this phenomenon can be exploited for cancer therapy using inhibitors of FASN, with particular emphasis on orlistat as a repurposing drug., Expert Opinion: Disease stabilization only has been observed with a highly selective FASN inhibitor used as a single agent in clinical trials. It is too early to say whether the absence of tumor responses other than stabilization results because even full inhibition of FASN is not enough to elicit antitumor responses. The FASN inhibitor orlistat is a 'dirty' drug with target-off actions upon at least seven targets with a proven role in tumor biology. The development of orlistat formulations suited for its intravenous administration is a step ahead to shed light on the concept that drug promiscuity can or not be a virtue.
- Published
- 2018
- Full Text
- View/download PDF
16. Feasibility and antitumor efficacy in vivo , of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer.
- Author
-
Cervantes-Madrid D, Dominguez-Gomez G, Gonzalez-Fierro A, Perez-Cardenas E, Taja-Chayeb L, Trejo-Becerril C, and Duenas-Gonzalez A
- Abstract
The aim of the present study was to investigate in vivo the feasibility and efficacy of the combination of lonidamine (LND), 6-diazo-5-oxo-L-norleucine (DON) and orlistat to simultaneously target glycolysis, glutaminolysis and de novo synthesis of fatty acids, respectively. The doses of LND and DON used in humans were translated to mouse doses (77.7 mg/kg and 145.5 mg/kg, respectively) and orlistat was used at 240 mg/kg. Three schedules of LND, DON and orlistat at different doses were administered by intraperitoneal injection to BALB/c mice in a 21-day cycle (schedule 1: LND, 0.5 mg/day; DON, 0.25 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 2: LND, 0.1 mg/day; DON, 0.5 mg/day 1, 5 and 9; orlistat, 240 mg/kg/day; schedule 3: LND, 0.5 mg/day; DON, 0.08 mg/day 1, 5 and 9; orlistat, 360 mg/kg/day) to assess tolerability. To determine the antitumor efficacy, a syngeneic tumor model in BALB/c mice was created using colon cancer CT26.WT cells, and a xenogeneic tumor model was created in nude mice using the human colon cancer SW480 cell line. Mice were treated with schedule 1. Animals were weighed, clinically inspected during the experiment and the tumor volume was measured at day 21. The 3 schedules assessed in the tolerability experiments were well tolerated, as mice maintained their weight and no evident clinical signs of toxicity were observed. Combination treatment with schedule 1 significantly decreased tumor growth in each mouse model. No evident signs of toxicity were observed and mice maintained their weight during treatment. The triple metabolic blockade of the malignant phenotype appears feasible and promising for cancer therapy.
- Published
- 2017
- Full Text
- View/download PDF
17. Antitumor Effects of Systemic DNAse I and Proteases in an In Vivo Model.
- Author
-
Trejo-Becerril C, Pérez-Cardenas E, Gutiérrez-Díaz B, De La Cruz-Sigüenza D, Taja-Chayeb L, González-Ballesteros M, García-López P, Chanona J, and Dueñas-González A
- Subjects
- Adult, Animals, Breast Neoplasms blood, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic metabolism, Colonic Neoplasms blood, Colonic Neoplasms drug therapy, Colonic Neoplasms metabolism, DNA blood, Female, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Proteins metabolism, Rats, Rats, Wistar, Deoxyribonuclease I pharmacology, Peptide Hydrolases pharmacology
- Abstract
Background Cell-free DNA circulates in cancer patients and induces in vivo cell transformation and cancer progression in susceptible cells. Based on this, we hypothesized that depletion of circulating DNA with DNAse I and a protease mix could have antitumor effects. Study design The study aimed to demonstrate that DNAse I and a protease mix can degrade in vitro DNA and proteins from the serum of healthy individuals and cancer patients, and in vivo in serum of Wistar rats,. Moreover, the antitumor effect of the systemically administered enzyme mix treatmentwas evaluated in nude mice subcutaneously grafted with the human colon cancer cell line SW480. Results The serum DNA of cancer patients or healthy individuals was almost completely degraded in vitro by the enzymatic treatment, but no degradation was found with the enzymes given separately. The intravenous administration of the enzymes led to significant decreases in DNA and proteins from rat serum. No antitumor effect was observed in immunodeficient mice treated with the enzymes given separately. In contrast, the animals that received both enzymes exhibited a marked growth inhibition of tumors, 40% of them having pathological complete response. Conclusion This study demonstrated that systemic treatment with DNAse I and a protease mix in rats decreases DNA and proteins from serum and that this treatment has antitumor effects. Our results support the hypothesis that circulating DNA could have a role in tumor progression, which can be offset by depleting it. Further studies are needed to prove this concept., (© The Author(s) 2016.)
- Published
- 2016
- Full Text
- View/download PDF
18. Viral inhibitors of NKG2D ligands for tumor surveillance.
- Author
-
Chávez-Blanco A, Chacón-Salinas R, Dominguez-Gomez G, Gonzalez-Fierro A, Perez-Cardenas E, Taja-Chayeb L, Trejo-Becerril C, and Duenas-Gonzalez A
- Subjects
- Antiviral Agents pharmacology, Humans, Immunity, Innate immunology, Killer Cells, Natural immunology, Ligands, NK Cell Lectin-Like Receptor Subfamily K immunology, Neoplasms immunology, Neoplasms therapy, Neoplasms virology, Signal Transduction immunology, Virus Diseases complications, Virus Diseases immunology, Virus Diseases therapy, Immunotherapy methods, Killer Cells, Natural metabolism, NK Cell Lectin-Like Receptor Subfamily K metabolism
- Abstract
Introduction: Natural Killer cells (NK) are key for the innate immune response against tumors and viral infections. Several viral proteins evade host immune response and target the NK cell receptor NKG2D and its ligands. Areas covered: This review aimed to describe the viruses and their proteins that interfere with the NKG2D receptor and their ligands, and how these interactions lead to immune evasion, host protection, and tissue damage from acute and chronic viral infections. Expert opinion: The study of viral proteins has already impacted the field of oncology. A prime example is the HBV vaccine and the development of antiviral drugs for HIV, Hepatitis C, and the family of Herpesviridae viruses. The NKG2D system seems to be a rational therapeutic target. Nevertheless, an effective cytotoxic response by NK cells is mediated by a network of activating and inhibitory receptors, the integration of which determines if the NK cell becomes cytotoxic or permissive. Immunotherapeutic agents that increase the antitumor lytic activity of NK cells through modulating activation and inhibitory signaling of NK cells are being developed. Nevertheless, more research is needed to dissect the integrative mechanism of NK cells function to fully exploit their antitumor and antiviral effector mechanisms.
- Published
- 2016
- Full Text
- View/download PDF
19. In vivo rat model to study horizontal tumor progression.
- Author
-
Trejo-Becerril C, Pérez-Cárdenas E, and Dueñas-González A
- Subjects
- Animals, Cell Line, Tumor, DNA blood, DNA genetics, Disease Models, Animal, Female, Humans, In Situ Hybridization, Fluorescence, Microdissection, Neoplasms blood, Polymerase Chain Reaction, Rats, Rats, Wistar, Sequence Analysis, DNA, Disease Progression, Gene Transfer Techniques, Neoplasms genetics, Neoplasms pathology
- Abstract
Most cancer deaths are due to metastases. Metastasis is an extraordinarily complex process by which cancer cells complete a sequential series of steps before they transform into a clinically detectable lesion. These steps typically include separation from the primary tumor, invasion through surrounding tissues and basement membranes, entry and survival in the circulation, lymphatic or peritoneal space, and arrest in a distant target organ and the formation of secondary tumors in distant organs.While proposed or accepted models and mechanisms of metastatic progression, have been demonstrated in experimental systems, none of them sufficiently explain all of the complexities associated with this process. These models can broadly be classified into two types, those occurring by vertical gene transfer (Darwinian) and those involving horizontal or lateral DNA transfer. Here, we describe an experimental system to study the metastatic process involving the horizontal transfer of circulating DNA.
- Published
- 2014
- Full Text
- View/download PDF
20. Cancer progression mediated by horizontal gene transfer in an in vivo model.
- Author
-
Trejo-Becerril C, Pérez-Cárdenas E, Taja-Chayeb L, Anker P, Herrera-Goepfert R, Medina-Velázquez LA, Hidalgo-Miranda A, Pérez-Montiel D, Chávez-Blanco A, Cruz-Velázquez J, Díaz-Chávez J, Gaxiola M, and Dueñas-González A
- Subjects
- Animals, Base Sequence, Cell Line, Tumor, Culture Media, Conditioned chemistry, Disease Models, Animal, Female, Gene Dosage, Genes, ras, Humans, Mice, NIH 3T3 Cells, Rats, rab GTP-Binding Proteins chemistry, rab GTP-Binding Proteins genetics, Cell Transformation, Neoplastic genetics, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Gene Transfer, Horizontal
- Abstract
It is known that cancer progresses by vertical gene transfer, but this paradigm ignores that DNA circulates in higher organisms and that it is biologically active upon its uptake by recipient cells. Here we confirm previous observations on the ability of cell-free DNA to induce in vitro cell transformation and tumorigenesis by treating NIH3T3 recipient murine cells with serum of colon cancer patients and supernatant of SW480 human cancer cells. Cell transformation and tumorigenesis of recipient cells did not occur if serum and supernatants were depleted of DNA. It is also demonstrated that horizontal cancer progression mediated by circulating DNA occurs via its uptake by recipient cells in an in vivo model where immunocompetent rats subjected to colon carcinogenesis with 1,2-dimethylhydrazine had increased rate of colonic tumors when injected in the dorsum with human SW480 colon carcinoma cells as a source of circulating oncogenic DNA, which could be offset by treating these animals with DNAse I and proteases. Though the contribution of biologically active molecules other than DNA for this phenomenon to occur cannot be ruled out, our results support the fact that cancer cells emit into the circulation biologically active DNA to foster tumor progression. Further exploration of the horizontal tumor progression phenomenon mediated by circulating DNA is clearly needed to determine whether its manipulation could have a role in cancer therapy.
- Published
- 2012
- Full Text
- View/download PDF
21. DNA methylation-independent reversion of gemcitabine resistance by hydralazine in cervical cancer cells.
- Author
-
Candelaria M, de la Cruz-Hernandez E, Taja-Chayeb L, Perez-Cardenas E, Trejo-Becerril C, Gonzalez-Fierro A, Chavez-Blanco A, Soto-Reyes E, Dominguez G, Trujillo JE, Diaz-Chavez J, and Duenas-Gonzalez A
- Subjects
- Antimetabolites, Antineoplastic therapeutic use, Blotting, Western, Cell Culture Techniques, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA Primers genetics, Deoxycytidine metabolism, Deoxycytidine therapeutic use, Equilibrative Nucleoside Transporter 1 metabolism, Female, Histocompatibility Antigens, Histone Deacetylases metabolism, Histone-Lysine N-Methyltransferase antagonists & inhibitors, Humans, Reverse Transcriptase Polymerase Chain Reaction, Gemcitabine, Antimetabolites, Antineoplastic metabolism, Deoxycytidine analogs & derivatives, Drug Resistance, Neoplasm drug effects, Epigenesis, Genetic physiology, Gene Expression Regulation, Neoplastic physiology, Hydralazine pharmacology, Uterine Cervical Neoplasms drug therapy
- Abstract
Background: Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells., Methodology/principal Findings: The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity., Conclusions/significance: Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase.
- Published
- 2012
- Full Text
- View/download PDF
22. Acetylator status and N-acetyltransferase 2 gene polymorphisms; phenotype-genotype correlation with the sulfamethazine test.
- Author
-
Taja-Chayeb L, González-Fierro A, Miguez-Muñoz C, Trejo-Becerril C, Cruz-Hernandez Ede L, Cantu D, Agundez JA, Vidal-Millan S, Gutierrez O, and Dueñas-González A
- Subjects
- Acetylation, Adult, Aged, Alleles, Arylamine N-Acetyltransferase metabolism, Female, Genetic Association Studies, Humans, Male, Mexico, Middle Aged, Neoplasms genetics, Neoplasms metabolism, Arylamine N-Acetyltransferase genetics, Carcinogens pharmacology, Polymorphism, Genetic, Sulfamethazine pharmacokinetics
- Abstract
N-acetyltransferase 2 (NAT2) catalyzes the bioactivation and/or detoxification of drugs and carcinogens. The aim of this study was to establish the correlation between the NAT2 genotype and the acetylating phenotype in a Mexican population using sulfamethazine as a probe. From a total of 122 individuals, 73 (59.8%) were slow and 49 (40.2%) were fast acetylators. Eleven individuals (9%) had the wild-type genotype (NAT2*4/NAT2*4). The most frequent genotype was NAT2*4/NAT2*5B observed in 20.66% of individuals. In conclusion, our results show that an accurate prediction of the acetylation phenotype by genotyping can be achieved in around half of the population. Further studies with a larger number of individuals are required to establish correlations between phenotype and genotype in half of that patients having a genotype combined with slow/rapid alleles.
- Published
- 2011
- Full Text
- View/download PDF
23. A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results.
- Author
-
Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, González-Fierro A, de la Cruz-Hernandez E, Perez-Cardenas E, Taja-Chayeb L, Arias-Bofill D, Candelaria M, Vidal S, and Dueñas-González A
- Subjects
- Adult, Aged, Combined Modality Therapy methods, Double-Blind Method, Female, Follow-Up Studies, Humans, Hydralazine administration & dosage, Middle Aged, Survival Rate, Uterine Cervical Neoplasms mortality, Valproic Acid administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Epigenesis, Genetic, Genetic Therapy methods, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms therapy
- Abstract
The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze.
- Published
- 2011
- Full Text
- View/download PDF
24. Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate.
- Author
-
Chávez-Blanco A, De la Cruz-Hernández E, Domínguez GI, Rodríguez-Cortez O, Alatorre B, Pérez-Cárdenas E, Chacón-Salinas R, Trejo-Becerril C, Taja-Chayeb L, Trujillo JE, Contreras-Paredes A, and Dueñas-González A
- Subjects
- Cell Line, Tumor, Histocompatibility Antigens Class I genetics, Humans, Ligands, Neoplasms genetics, Neoplasms immunology, Protein Binding immunology, Antineoplastic Agents pharmacology, Cytotoxicity, Immunologic drug effects, Hydralazine pharmacology, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, NK Cell Lectin-Like Receptor Subfamily K metabolism, Up-Regulation drug effects, Valproic Acid pharmacology
- Abstract
Natural killer cells play a role in the immune antitumor response by recognizing and eliminating tumor cells through the engagement of NKG2D receptors with their ligands on target cells. This work aimed to investigate whether epigenetic drugs are able to increase MICA and MICB expression as well as NK cell cytotoxicity. Prostate, colon, breast and cervical cancer cell lines were analyzed for the expression of MICA and MICB at the mRNA and protein levels by RT-PCR, Western blot, flow cytometry and ELISA. The activating mark H3K4m2 at the MICA and MICB promoters was investigated by ChIP assays. Cytotoxicity of NK cells against the target epithelial cancer cells was investigated with the CD107 cytotoxicity assay. The results show that hydralazine and valproic acid not only increase the expression of MICA and MICB ligands of target cells, but also reduce their shedding to the supernatant. This upregulation occurs at the transcriptional level as revealed by increase of the H3K4 activating mark at the promoter of MICA and MICB genes. These effects are paralleled by increased cytotoxicity of NK cells, which was attenuated at different degrees by using blocking antibodies against the NKG2D receptor and ligands. In conclusion, our results demonstrate the ability of hydralazine and valproate to increase the NK activity against epithelial cancer cell lines and suggest that these drugs could reduce the levels of soluble MICA and MICB helping in avoiding tumor-induced suppression of NK cytotoxicity against the tumor.
- Published
- 2011
- Full Text
- View/download PDF
25. Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial.
- Author
-
Candelaria M, Herrera A, Labardini J, González-Fierro A, Trejo-Becerril C, Taja-Chayeb L, Pérez-Cárdenas E, de la Cruz-Hernández E, Arias-Bofill D, Vidal S, Cervera E, and Dueñas-Gonzalez A
- Subjects
- Adult, Aged, Azacitidine analogs & derivatives, Azacitidine therapeutic use, Cytogenetic Analysis, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, DNA Modification Methylases antagonists & inhibitors, Decitabine, Female, Histone Deacetylase Inhibitors blood, Histone Deacetylase Inhibitors therapeutic use, Humans, Hydralazine blood, Kaplan-Meier Estimate, Male, Middle Aged, Myelodysplastic Syndromes blood, Treatment Outcome, Valproic Acid blood, Young Adult, Epigenomics, Hydralazine therapeutic use, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Valproic Acid therapeutic use
- Abstract
Decitabine and azacitidine, two DNA methyltransferase (DNMT) inhibitors, are the current standard of treatment for myelodysplastic syndrome (MDS). Histone deacetylase (HDAC) inhibitors are also being tested against MDS. Both drug classes synergize in their gene reactivating and anticancer activities. The combination of hydralazine and valproate (Transkrip®), a DNMT and HDAC inhibitor, respectively), has been developed as epigenetic therapy under the drug repositioning concept. To evaluate the clinical efficacy and safety of hydralazine and valproate against MDS, an open phase-II study for previously treated patients with MDS was conducted. The hydralazine dose was given according with the acetylator phenotype, and valproate was dosed at 30 mg/kg/day. Response was graded with International Working Group criteria. Toxicity was evaluated by the Common Toxemia Criteria-National Cancer Institute version 3 scale. From November 2007 to January 2010, 12 patients were included. Median age±SD was 53±19.78 years (range, 23-79 years); median time from diagnosis to inclusion in the study was 7.9 months (range 2.6-36.1 months). Median of previous treatment was 2 (range, 1-6). Refractory cytopenia with multilineage dysplasia was diagnosed in ten cases, and refractory anemia with excess of blasts in two. Overall response was documented in six (50%) of 12 cases, including one CR, one PR, and four hematological improvements of the erythroid series. Two patients (16.6%) progressed to acute myeloid leukemia. Hemoglobin increased from 7.4 to 10.3 g/dL (in 13 weeks), neutrophils, from 1.1 to 2.0 (in 3 weeks), and platelets, from 66×10(9) to 72×10(9)/L (in 2 weeks). Transfusional requirements decreased from 2.3 to 0 U bi-monthly for red blood cells and from 0.5 to 0 U bi-monthly for platelets in responding patients. Main toxicities were mild, including somnolence and nausea. Preliminary results of this phase-II study suggest that the combination of hydralazine and valproate is a promising non-toxic and effective therapy for MDS.
- Published
- 2011
- Full Text
- View/download PDF
26. Transcriptional changes induced by epigenetic therapy with hydralazine and magnesium valproate in cervical carcinoma.
- Author
-
De la Cruz-Hernández E, Perez-Plasencia C, Pérez-Cardenas E, Gonzalez-Fierro A, Trejo-Becerril C, Chávez-Blanco A, Taja-Chayeb L, Vidal S, Gutiérrez O, Dominguez GI, Trujillo JE, and Duenas-González A
- Subjects
- Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma drug therapy, Carcinoma pathology, Clinical Trials as Topic, DNA Methylation drug effects, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Histone Deacetylase Inhibitors administration & dosage, Histone Deacetylase Inhibitors pharmacology, Humans, Hydralazine administration & dosage, Microarray Analysis, Up-Regulation drug effects, Up-Regulation genetics, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms pathology, Valproic Acid administration & dosage, Carcinoma genetics, Epigenesis, Genetic drug effects, Hydralazine pharmacology, Transcription, Genetic drug effects, Uterine Cervical Neoplasms genetics, Valproic Acid pharmacology
- Abstract
Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases is a promising cancer therapy. Experimental data demonstrate that these inhibitors in combination do not only show synergy in antitumor effects but also in whole genome global expression. Ten pairs of pre- and post-treatment cervical tumor samples were analyzed by microarray analysis. Treatment for seven days with hydralazine and valproate (HV) in patients up-regulated 964 genes. The two pathways possessing the highest number of up-regulated genes comprised the ribosome protein and the oxidative phosphorylation pathways, followed by MAPK signaling, tight junction, adherens junction, actin cytoskeleton, cell cycle, focal adhesion, apoptosis, proteasome, Wnt signaling, and antigen processing and presentation pathways. Up-regulated genes by HV, clustered with down-regulated genes in untreated primary cervical carcinomas and were more alike as compared with up-regulated genes from untreated patients in terms of gene ontology. Increased acetylated p53 was also observed. Epigenetic therapy with HV leads to gene reactivation in primary tumors of cervical cancer patients as well as protein acetylation. A number of these reactivated genes have a definitive role as a tumor suppressors. The global expression pattern induced by HV suggests this therapy has an impact on pathways related to energy production which may promote apoptosis.
- Published
- 2011
- Full Text
- View/download PDF
27. Identification of a novel germ-line mutation in the TP53 gene in a Mexican family with Li-Fraumeni syndrome.
- Author
-
Taja-Chayeb L, Vidal-Millán S, Gutiérrez-Hernández O, Trejo-Becerril C, Pérez-Cárdenas E, Chávez-Blanco A, de la Cruz-Hernández E, and Dueñas-González A
- Subjects
- Adult, Aged, DNA Primers chemistry, DNA Primers genetics, Female, Humans, Male, Mexico, Middle Aged, Pedigree, Young Adult, Germ-Line Mutation genetics, Li-Fraumeni Syndrome genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Background: Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors., Methods: Mutation analysis was based on Denaturing high performance liquid chromatography (DHPLC) screening of exons 2-11 of the TP53 gene, sequencing, and cloning of DNA obtained from peripheral blood lymphocytes., Results: We report herein on Li Fraumeni syndrome in a family whose members are carriers of a novel TP53 gene mutation at exon 4. The mutation comprises an insertion/duplication of seven nucleotides affecting codon 110 and generating a new nucleotide sequence and a premature stop codon at position 150. With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain., Conclusion: To our knowledge, this specific alteration has not been reported previously, but we believe it is the cause of the Li-Fraumeni syndrome in this family.
- Published
- 2009
- Full Text
- View/download PDF
28. A proof-of-principle study of epigenetic therapy added to neoadjuvant doxorubicin cyclophosphamide for locally advanced breast cancer.
- Author
-
Arce C, Pérez-Plasencia C, González-Fierro A, de la Cruz-Hernández E, Revilla-Vázquez A, Chávez-Blanco A, Trejo-Becerril C, Pérez-Cárdenas E, Taja-Chayeb L, Bargallo E, Villarreal P, Ramírez T, Vela T, Candelaria M, Camargo MF, Robles E, and Dueñas-González A
- Subjects
- Adult, Aged, Breast Neoplasms pathology, DNA Methylation drug effects, Female, Gene Expression drug effects, Histone Deacetylase Inhibitors administration & dosage, Humans, Hydralazine administration & dosage, Middle Aged, Neoadjuvant Therapy, Valproic Acid administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Epigenesis, Genetic drug effects
- Abstract
Background: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy., Methodology: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day -7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate., Main Findings: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1-2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively., Conclusions: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.
- Published
- 2006
- Full Text
- View/download PDF
29. Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines.
- Author
-
Chavez-Blanco A, Perez-Plasencia C, Perez-Cardenas E, Carrasco-Legleu C, Rangel-Lopez E, Segura-Pacheco B, Taja-Chayeb L, Trejo-Becerril C, Gonzalez-Fierro A, Candelaria M, Cabrera G, and Duenas-Gonzalez A
- Abstract
Background: Among the epigenetic alterations occurring in cancer, DNA hypermethylation and histone hypoacetylation are the focus of intense research because their pharmacological inhibition has shown to produce antineoplastic activity in a variety of experimental models. The objective of this study was to evaluate the combined antineoplastic effect of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in a panel of cancer cell lines., Results: Hydralazine showed no growth inhibitory effect on cervical, colon, breast, sarcoma, glioma, and head & neck cancer cell lines when used alone. On the contrary, valproic acid showed a strong growth inhibitory effect that is potentiated by hydralazine in some cell lines. Individually, hydralazine and valproic acid displayed distinctive effects upon global gene over-expression but the number of genes over-expressed increased when cells were treated with the combination. Treatment of HeLa cells with hydralazine and valproic acid lead to an increase in the cytotoxicity of gemcitabine, cisplatin and adriamycin. A higher antitumor effect of adriamycin was observed in mice xenografted with human fibrosarcoma cells when the animals were co-treated with hydralazine and valproic acid., Conclusion: Hydralazine and valproic acid, two widely used drugs for cardiovascular and neurological conditions respectively have promising antineoplastic effects when used concurrently and may increase the antitumor efficacy of current cytotoxic agents.
- Published
- 2006
- Full Text
- View/download PDF
30. Response to gefitinib in bronchioloalveolar carcinoma in the absence of EGFR mutation.
- Author
-
Taja-Chayeb L, Candelaria M, Brom R, Trejo-Becerril C, Meza F, and Duenas-Gonzalez A
- Subjects
- Adenocarcinoma, Bronchiolo-Alveolar genetics, Aged, Antineoplastic Agents pharmacology, DNA Mutational Analysis, Drug Resistance, Neoplasm, Female, Gefitinib, Humans, Lung Neoplasms genetics, Protein-Tyrosine Kinases genetics, Quinazolines pharmacology, Treatment Outcome, Adenocarcinoma, Bronchiolo-Alveolar drug therapy, Antineoplastic Agents therapeutic use, ErbB Receptors genetics, Lung Neoplasms drug therapy, Quinazolines therapeutic use
- Abstract
Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity such as gefitinib and erlotinib. Responses to TK inhibitors in the absence of EGFR gene mutation for BAC patients have not been reported. A case of a patient with BAC refractory to chemotherapy who responded to gefitinib in the absence of EGFR gene mutations is reported. Tyrosine kinase inhibitors may have a role in BAC in the absence of EGFR gene mutations. Additional studies on other molecular alterations of the EGFR family members are needed to better predict response to these agents.
- Published
- 2005
- Full Text
- View/download PDF
31. Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study.
- Author
-
Chavez-Blanco A, Segura-Pacheco B, Perez-Cardenas E, Taja-Chayeb L, Cetina L, Candelaria M, Cantu D, Gonzalez-Fierro A, Garcia-Lopez P, Zambrano P, Perez-Plasencia C, Cabrera G, Trejo-Becerril C, Angeles E, and Duenas-Gonzalez A
- Subjects
- Acetylation, Adult, Aged, Dose-Response Relationship, Drug, Female, Humans, Middle Aged, Neoplasm Staging, Uterine Cervical Neoplasms blood, Uterine Cervical Neoplasms pathology, Valproic Acid adverse effects, Valproic Acid pharmacokinetics, Histone Deacetylases metabolism, Histones metabolism, Leukocytes metabolism, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms metabolism, Valproic Acid blood, Valproic Acid therapeutic use
- Abstract
Background: The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest., Methods: Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period., Results: All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6-170.49 microg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid., Conclusion: Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.
- Published
- 2005
- Full Text
- View/download PDF
32. Serum nucleosomes during neoadjuvant chemotherapy in patients with cervical cancer. Predictive and prognostic significance.
- Author
-
Trejo-Becerril C, Oñate-Ocaña LF, Taja-Chayeb L, Vanoye-Carlo A, Cetina L, and Duenas-Gonzalez A
- Subjects
- Adolescent, Adult, Aged, Carboplatin administration & dosage, Chemotherapy, Adjuvant, Cohort Studies, Confidence Intervals, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Enzyme-Linked Immunosorbent Assay, Female, Humans, Hysterectomy methods, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Paclitaxel administration & dosage, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Risk Assessment, Sensitivity and Specificity, Survival Analysis, Treatment Outcome, Uterine Cervical Neoplasms mortality, Uterine Cervical Neoplasms surgery, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor blood, Nucleosomes metabolism, Uterine Cervical Neoplasms blood, Uterine Cervical Neoplasms drug therapy
- Abstract
Background: It has been shown that free DNA circulates in serum plasma of patients with cancer and that at least part is present in the form of oligo- and monucleosomes, a marker of cell death. Preliminary data has shown a good correlation between decrease of nucleosomes with response and prognosis. Here, we performed pre- and post-chemotherapy determinations of serum nucleosomes with an enzyme-linked immunosorbent assay (ELISA) method in a group of patients with cervical cancer receiving neoadjuvant chemotherapy., Methods: From December 2000 to June 2001, 41 patients with cervical cancer staged as FIGO stages IB2-IIIB received three 21-day courses of carboplatin and paclitaxel, both administered at day 1; then, patients underwent radical hysterectomy. Nucleosomes were measured the day before (baseline), at day seven of the first course and day seven of the third course of chemotherapy. Values of nucleosomes were analyzed with regard to pathologic response and to time to progression-free and overall survival., Results: All patients completed chemotherapy, were evaluable for pathologic response, and had nucleosome levels determined. At a mean follow-up of 23 months (range, 7-26 months), projected progression time and overall survival were 80.3 and 80.4%, respectively. Mean differential values of nucleosomes were lower in the third course as compared with the first course (p >0.001). The decrease in the third course correlated with pathologic response (p = 0.041). Survival analysis showed a statistically significant, better progression-free and survival time in patients who showed lower levels at the third course (p = 0.0243 and p = 0.0260, respectively). Cox regression analysis demonstrated that nucleosome increase in the third course increased risk of death to 6.86 (95% confidence interval [CI 95%], 0.84-56.0)., Conclusion: Serum nucleosomes may have a predictive role for response and prognostic significance in patients with cervical cancer patients treated with neoadjuvant chemotherapy.
- Published
- 2005
- Full Text
- View/download PDF
33. A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes.
- Author
-
Zambrano P, Segura-Pacheco B, Perez-Cardenas E, Cetina L, Revilla-Vazquez A, Taja-Chayeb L, Chavez-Blanco A, Angeles E, Cabrera G, Sandoval K, Trejo-Becerril C, Chanona-Vilchis J, and Duenas-González A
- Subjects
- 5-Methylcytosine pharmacology, Adult, Aged, Binding Sites, Biopsy, Cohort Studies, Cytosine chemistry, DNA genetics, Electrophoresis, Capillary, Female, Humans, Middle Aged, Promoter Regions, Genetic, RNA, Long Noncoding, RNA, Untranslated genetics, Reverse Transcriptase Polymerase Chain Reaction, Vasodilator Agents pharmacology, Cardiovascular Diseases drug therapy, DNA Methylation drug effects, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Hydralazine pharmacology, Uterine Cervical Neoplasms drug therapy, Uterine Cervical Neoplasms genetics
- Abstract
Background: The antihypertensive compound hydralazine is a known demethylating agent. This phase I study evaluated the tolerability and its effects upon DNA methylation and gene reactivation in patients with untreated cervical cancer., Methods: Hydralazine was administered to cohorts of 4 patients at the following dose levels: I) 50 mg/day, II) 75 mg/day, III) 100 mg/day and IV) 150 mg/day. Tumor biopsies and peripheral blood samples were taken the day before and after treatment. The genes APC, MGMT; ER, GSTP1, DAPK, RARbeta, FHIT and p16 were evaluated pre and post-treatment for DNA promoter methylation and gene expression by MSP (Methylation-Specific PCR) and RT-PCR respectively in each of the tumor samples. Methylation of the imprinted H19 gene and the "normally methylated" sequence clone 1.2 was also analyzed. Global DNA methylation was analyzed by capillary electrophoresis and cytosine extension assay. Toxicity was evaluated using the NCI Common Toxicity Criteria., Results: Hydralazine was well tolerated. Toxicities were mild being the most common nausea, dizziness, fatigue, headache and palpitations. Overall, 70% of the pretreatment samples and all the patients had at least one methylated gene. Rates of demethylation at the different dose levels were as follows: 50 mg/day, 40%; 75 mg/day, 52%, 100 mg/day, 43%, and 150 mg/day, 32%. Gene expression analysis showed only 12 informative cases, of these 9 (75%) re-expressed the gene. There was neither change in the methylation status of H19 and clone 1.2 nor changes in global DNA methylation., Conclusion: Hydralazine at doses between 50 and 150 mg/day is well tolerated and effective to demethylate and reactivate the expression of tumor suppressor genes without affecting global DNA methylation.
- Published
- 2005
- Full Text
- View/download PDF
34. [Association between presence of anti-Ras and anti-VPH16 E4/E7 antibodies and cervical intraepithelial lesions].
- Author
-
Vázquez-Corzo S, Trejo-Becerril C, Cruz-Valdez A, Hernández-Nevarez P, Esquivel-Guadarrama R, and Gutiérrez-Xicotencatl Mde L
- Subjects
- Adult, Aged, Case-Control Studies, Female, Humans, Middle Aged, Papillomavirus E7 Proteins, Prevalence, Risk Factors, Seroepidemiologic Studies, Uterine Cervical Neoplasms epidemiology, Uterine Cervical Neoplasms immunology, Antibodies blood, Biomarkers, Tumor blood, Oncogene Proteins, Viral immunology, Uterine Cervical Neoplasms blood, ras Proteins immunology
- Abstract
Objective: To evaluate whether serum antibodies anti-E4, E7 and Ras could be used as markers for early cervical lesions associated with HPV (human papillomavirus)., Material and Methods: A seroepidemiological case-control study was conducted between March 1999 and April 2000 at the dysplasia clinic of Hospital General Doctor Gea Gonzalez, in Mexico City, to evaluate the presence of antibodies anti-E4, E7, and Ras through a sandwich ELISA. Analysis was done using odds ratios and 95% confidence intervals., Results: Anti-E7 antibodies were associated to women with CIN III lesions, while anti-E4 and Ras antibodies were strongly associated with CIN I-II lesions. The antibody profile of women with different cervical lesion showed that: a) the presence of antibodies against two proteins predicts the presence of CIN I-II lesions, and b) the presence of three antibodies predicts a CIN III lesion., Conclusions: The presence of serum antibodies against E4, E7 and Ras, together with other diagnostic techniques, could be useful for the timely detection of early uterine cervical lesions associated to HPV in women at risk of developing cancer.
- Published
- 2003
35. Circulating nucleosomes and response to chemotherapy: an in vitro, in vivo and clinical study on cervical cancer patients.
- Author
-
Trejo-Becerril C, Pérez-Cárdenas E, Treviño-Cuevas H, Taja-Chayeb L, García-López P, Segura-Pacheco B, Chávez-Blanco A, Lizano-Soberon M, González-Fierro A, Mariscal I, Wegman-Ostrosky T, and Dueñas-González A
- Subjects
- Adenocarcinoma blood, Adenocarcinoma drug therapy, Adult, Aged, Animals, Carcinoma, Adenosquamous blood, Carcinoma, Adenosquamous drug therapy, Carcinoma, Squamous Cell blood, Carcinoma, Squamous Cell drug therapy, Case-Control Studies, Cisplatin therapeutic use, Deoxycytidine administration & dosage, Enzyme-Linked Immunosorbent Assay, Female, HeLa Cells, Humans, In Vitro Techniques, Mice, Mice, Nude, Middle Aged, Neoadjuvant Therapy, Organoplatinum Compounds administration & dosage, Oxaliplatin, Paclitaxel administration & dosage, Papillomaviridae pathogenicity, Papillomavirus Infections blood, Papillomavirus Infections drug therapy, Prognosis, Rats, Rats, Wistar, Tumor Virus Infections blood, Tumor Virus Infections drug therapy, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, DNA, Neoplasm blood, DNA, Viral blood, Deoxycytidine analogs & derivatives, Neoplastic Cells, Circulating metabolism, Nucleosomes metabolism, Uterine Cervical Neoplasms blood, Uterine Cervical Neoplasms drug therapy
- Abstract
It is known that cell-free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre- and post-treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor-free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6-12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre- and post-treatment could be a useful test to predict response to chemotherapy in cancer patients., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
- Full Text
- View/download PDF
36. Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy.
- Author
-
Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E, Taja-Chayeb L, Mariscal I, Chavez A, Acuña C, Salazar AM, Lizano M, and Dueñas-Gonzalez A
- Subjects
- Animals, Antimetabolites, Antineoplastic pharmacology, Azacitidine pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cell Cycle drug effects, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Decitabine, Enzyme Inhibitors pharmacology, Female, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms drug therapy, Humans, Mice, Mice, Nude, Receptors, Estrogen metabolism, Receptors, Retinoic Acid genetics, Tumor Cells, Cultured transplantation, Uterine Cervical Neoplasms drug therapy, Azacitidine analogs & derivatives, Breast Neoplasms genetics, DNA Methylation drug effects, Genes, Tumor Suppressor drug effects, Hydralazine pharmacology, Procainamide pharmacology
- Abstract
Purpose: The purpose of this study is to evaluate the demethylating and tumor suppressor-reactivating activity of hydralazine and procainamide., Experimental Design: MDA-231, MCF-7, and T24 cell lines were treated for 5 days with 10 micro M hydralazine or 10 micro M procainamide. 5-aza-deoxycytidine at 0.75 micro M was used as positive control. BALB/c nu/nu mice xenografted with MDA-231 cells were treated with these drugs for 7 days by i.p. route. Methylation was assessed by PCR after digestion with methylation-sensitive enzymes for the ER gene and with methylation-specific PCR for retinoic acid receptor (RAR)beta and p16 genes. Gene expression was evaluated by reverse transcription-PCR and Western blot. The duration of the gene re-expressing effect of hydralazine was analyzed on T24 cells. Functionality of the re-expressed proteins was evaluated by the induction of the estrogen-responsive gene PS2 on MDA-231 cells and by the induction of G(1) arrest on T24 cells. The gene demethylating and re-expressing ability of hydralazine was tested in two patients with cervical and head and neck carcinomas, respectively., Results: Hydralazine and procainamide induced de-methylation and re-expression of the ER, RARbeta, and p16 genes in cultured cells. Both drugs also demethylated and re-expressed the ER gene in mice. Hydralazine re-expressed the p16 gene longer as compared with 5-aza-deoxycytidine. The re-expressed genes were functional. In addition, the treatment with oral hydralazine demethylated and re-expressed the RARbeta and p16 genes in the cervical and head and cancer patients., Conclusions: These cardiovascular drugs have a promising tumor suppressor-reactivating action and could potentially be used in clinic as an anticancer treatment, most likely to increase the efficacy of current biological or chemotherapeutic treatments.
- Published
- 2003
37. Induction chemotherapy with gemcitabine and oxaliplatin for locally advanced cervical carcinoma.
- Author
-
Dueñas-González A, López-Graniel C, González A, Gomez E, Rivera L, Mohar A, Chanona G, Trejo-Becerril C, and de la Garza J
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma pathology, Adenocarcinoma radiotherapy, Adenocarcinoma surgery, Adult, Carcinoma, Adenosquamous drug therapy, Carcinoma, Adenosquamous pathology, Carcinoma, Adenosquamous radiotherapy, Carcinoma, Adenosquamous surgery, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell radiotherapy, Carcinoma, Squamous Cell surgery, Combined Modality Therapy, Deoxycytidine administration & dosage, Female, Humans, Middle Aged, Neoplasm Staging, Organoplatinum Compounds administration & dosage, Oxaliplatin, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms radiotherapy, Uterine Cervical Neoplasms surgery, Gemcitabine, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Deoxycytidine analogs & derivatives, Uterine Cervical Neoplasms drug therapy
- Abstract
Induction chemotherapy followed by surgery, particularly with newer agents or combinations, remains to be explored in locally advanced cervical cancer. Gemcitabine cisplatin is a very active combination for this tumor, therefore we explored the activity of gemcitabine in combination with oxaliplatin. Ten untreated patients with histologic diagnosis of cervical carcinoma and staged as IB2 to IIIB were treated with 3 21-day courses of oxaliplatin 130 mg/m day 1 and gemcitabine 1,250 mg/m days 1 and 8 followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated at the end of chemotherapy. All patients were evaluable. The overall clinical response rate was 80%, being complete in 3 patients (30%) and partial in 5 (50%). Seven (70%) patients underwent surgery, and three (30%) had chemoradiation as definitive treatment. Hematologic toxicity was moderate, with leukopenia grades III-IV in 17 and 0%; granulocytopenia grades III-IV in 23 and 3%, respectively. Eight patients had grade I oropharyngeal toxicity. At a median follow-up of 11 months (range: 10-12), all patients are disease free. Gemcitabine oxaliplatin is a very active and well-tolerated combination for locally advanced cervical cancer.
- Published
- 2003
- Full Text
- View/download PDF
38. Correlation of tumor growth index with early treatment response in cervical carcinoma.
- Author
-
Trejo-Becerril C, Rivera L, Chanona J, Segura B, Pérez E, López-Graniel C, Hinojosa-García L, and Dueñas-González A
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma therapy, Adult, Age Factors, Aged, Aged, 80 and over, Apoptosis physiology, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell therapy, Cell Division physiology, Chemotherapy, Adjuvant, Female, Humans, Immunoenzyme Techniques, Middle Aged, Neoplasm Staging, Proliferating Cell Nuclear Antigen metabolism, Radiotherapy Dosage, Treatment Outcome, Uterine Cervical Neoplasms metabolism, Uterine Cervical Neoplasms therapy, Adenocarcinoma pathology, Carcinoma, Squamous Cell pathology, Uterine Cervical Neoplasms pathology
- Abstract
Despite the recent progress in the management of cervical carcinoma, treatment failure is quite common and therefore it is necessary to identify predicting factors for tumor response. It is known that both cell proliferation and apoptosis determine the tumor growth index (TGI) which reflects the overall contribution of gene defects. Here we explored whether the TGI index could be a better predictor of response in comparison to cell proliferation or apoptosis as separate phenomena. Twenty-five patients with cervical carcinoma treated with radiation alone or neoadjuvant chemotherapy plus surgery were analyzed. Cell proliferation and apoptosis determined by PCNA immunohistochemical expression and tumor nucleosomes by ELISA, respectively, were used to calculate the TGI, which was analyzed with regard to early tumor response. Our results show that most patients with a negative TGI had early response suggesting increased tumor sensitivity(p = 0.0186). On the other hand, patients with a positive TGI were more resistant to treatment. TGI was not related to age, clinical stage or tumor size. In conclusion, the results of this study show that the determination of the TGI, but no cell proliferation or apoptosis, as separate events, is able to predict an early treatment response to either radiation or chemotherapy in cervical carcinoma.
- Published
- 2002
39. Membrane proteins in neoplasic and normal uterine cervix.
- Author
-
Trejo-Becerril C, Pérez-Cárdenas E, Taja-Chayeb L, Zeichner-Gancz I, Delgado-Chávez R, Solorza-Luna G, and Dueñas-González A
- Subjects
- Adult, Aged, Cervix Uteri metabolism, Electrophoresis, Polyacrylamide Gel, Female, Gene Expression Profiling, Humans, Middle Aged, Precancerous Conditions chemistry, Carcinoma, Squamous Cell chemistry, Membrane Proteins analysis, Neoplasm Proteins analysis, Uterine Cervical Neoplasms chemistry
- Abstract
Tumor cells exhibit phenotypic and genotypic differences in comparison to normal cells. These differences can be used to identify proteins important for tumor growth and, therefore, potentially used in the diagnosis and follow-up of patients. The objective of this work was to investigate the electrophoretic pattern of cytoplasm membrane proteins from normal and malignant cervix using polyacrylamide-SDS gels. A highly reproducible protein pattern was found in the 29 samples of normal cervix whereas three well-defined patterns of protein bands were observed in the 48 tumor specimens (pattern I: 25%, pattern II: 29.2% and pattern III: 45.8%). A low concentration or absence of high molecular weight proteins was observed (p<0.5) in tumor samples. None of the tumor protein patterns correlated with the clinicopathologic characteristics of patients. Nine out of 11 patients (82%) showing the pattern III had a complete clinical response whereas only 55% (11 out of 20) of those with patterns I and II showed a complete response. However, this difference was non-significant (p=0.1247). In conclusion, we demonstrate that there is a gain and loss of cytoplasmic membrane proteins in tumors, shown as different protein band patterns. These findings could have clinical and biological significance that must be further evaluated.
- Published
- 2001
40. Identification of peptides presented by HLA class I molecules on cervical cancer cells with HPV-18 infection.
- Author
-
García AM, Ortíz-Navarrete VF, Mora-García ML, Flores-Borja F, Diaz-Quiñonez A, Isibasi-Araujo A, Trejo-Becerril C, Chacón-Salinas R, Hernández-Montes J, Granados-Arreola J, de Leo C, and Weiss-Steider B
- Subjects
- Amino Acid Sequence, Antigens, Viral chemistry, Antigens, Viral immunology, Cytotoxicity, Immunologic, Epitopes immunology, Female, Histocompatibility Antigens Class I chemistry, Humans, Lymphocyte Activation, Mass Spectrometry, Molecular Sequence Data, Papillomavirus Infections immunology, Papillomavirus Infections virology, Peptides chemistry, Peptides isolation & purification, T-Lymphocytes immunology, Tumor Cells, Cultured, Tumor Virus Infections immunology, Tumor Virus Infections virology, Uterine Cervical Neoplasms immunology, Viral Proteins chemistry, Viral Proteins isolation & purification, Histocompatibility Antigens Class I immunology, Papillomaviridae immunology, Peptides immunology, Uterine Cervical Neoplasms virology, Viral Proteins immunology
- Abstract
In this work we eluted peptides from purified class I MHC molecules, isolated from a novel human cervical carcinoma cell line (INBL), generated in our laboratory and positive for HPV-18 infection. A fraction of these peptides was capable of stimulating T lymphocytes obtained from a donor matched for HLA-Cw4 and who was also HPV-18+. Direct N-terminal Edman degradation of these peptides, revealed the sequence (XQFPIFLQF) that matched 85% with the sequence NVFPIFLQM localized in between the 54 and 62 residues of the HPV-18 L1 protein. After stimulation with the synthetic peptide NVFPIFLQM, T lymphocytes from the donor were capable to lyse INBL cells. Our results provide evidence of the existence of naturally occurring viral epitopes presented on cervical cancer cells by the HLA-Cw4 allele, that could be useful for immunotherapy on this type of patient.
- Published
- 1999
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.