RESUMEN
AIM: The prevalence of genetic variants of thiopurine S-methyltransferse (TPMT) and dihydropyrimidine dehydrogenase (DPD) in healthy controls (500) and the treatment response in 500 cases of head and neck cancer of north Indian origin was studied. METHODS: Blood collected from all the subjects was used for isolation of DNA followed by genotyping studies. The cases received cisplatin and 5-fluorouracil (5-FU) or chemo-radiotherapy and treatment response was measured using WHO criteria. RESULTS: Low frequency of heterozygous mutant genotypes of TPMT*2 (2%), TPMT*3B (2.2%), TPMT*3C (4.6%), DPD IVS14+1G>A (3.6%) and G1601A (3%) was observed, although no homozygous mutants could be identified. Treatment response studies in cases receiving cisplatin and 5-FU or chemo-radiotherapy revealed that the number of nonresponders was higher in cases who carried variant genotypes of TPMT*3B (62.50%) or TPMT*3C (59.26%) or DPD IVS14+1G>A (61.90%). Likewise, the number of nonresponders was still higher in cases carrying combination of these genetic variants. Furthermore, the frequency of nonresponders was higher in cases who carried the variant genotypes of TPMT or DPD and were also tobacco users. CONCLUSIONS: Our data clearly show that TPMT and DPD genes are polymorphic in the north Indian population and may be important in determining the treatment response in cases. The data have also suggest tobacco may play an important role in determining the outcome of cancer therapy and there is an urgent need for assessment of drugs for their efficacy/toxicity in smokers compared to nonsmokers.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Células Escamosas/genética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Neoplasias de Cabeza y Cuello/genética , Metiltransferasas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/radioterapia , Estudios de Casos y Controles , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Frecuencia de los Genes , Genotipo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , India , Masculino , Metiltransferasas/metabolismo , Polimorfismo Genético , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
Head and neck squamous cell carcinoma (HNSCC) describes a wide range of malignant tumors which originate in the upper aerodigestive tract and have a multifactorial origin involving both genetic and lifestyle risk factors. The clinical management of head and neck cancer involves surgery, radiotherapy, and chemotherapy. With the advances in treatment strategies for HNSCC, newer targeted therapies are adding to the progress already achieved in the multimodality management of patients although the problems of differences in drug response and adverse drug reactions are still grave concerns. Cancer pharmacogenomics has fast emerged as a new and promising field for the early identification of genetic markers that can predict drug response or toxicity. This could greatly help in identifying genetic markers useful for the selection of optimal drugs, dose, and treatment duration on an individual basis resulting in improved drug efficacy and decreased toxicity. This review focuses on the various treatment modalities available for the clinical management of HNSCC followed by a description of the contribution of genetic variations to chemotherapeutic toxicity and response. Furthermore, studies addressing the association of genetic variants of drug-metabolizing enzymes with treatment response in head and neck cancer are also discussed.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/fisiopatología , Familia 2 del Citocromo P450/genética , Glutatión Transferasa/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/fisiopatología , Variantes Farmacogenómicas/genética , Antineoplásicos/uso terapéutico , Familia 2 del Citocromo P450/metabolismo , Medicina Basada en la Evidencia , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Glutatión Transferasa/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Medicina de Precisión/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
Genetic differences in susceptibility to cancer in subsites of the head and neck were investigated in a case-control study involving 750 cases of cancers of the oral cavity, larynx, or pharynx, and an equal number of healthy controls. The prevalence of variant genotypes of cytochrome P450 (CYP) 1A1, 1B1, 2E1, or glutathione-S-transferase M1 (null) in cases suggests that polymorphisms in drug metabolizing enzymes (DMEs) modify cancer risk within subsites of the head and neck. Tobacco or alcohol use was found to increase the risk in cases of laryngeal, pharyngeal, or oral cavity cancers. Interaction between genetic variation in DMEs and tobacco smoke (or smoking) exposures conferred significant risk for laryngeal cancer. Likewise, strong associations of the polymorphic genotypes of DMEs with cases of pharyngeal and oral cavity cancer who were tobacco chewers or alcohol users demonstrate that gene-environment interactions may explain differences in genetic susceptibility for cancers of the oral cavity, larynx, and pharynx.
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Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/genética , Adulto , Consumo de Bebidas Alcohólicas/efectos adversos , Estudios de Casos y Controles , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP2E1/genética , Femenino , Genotipo , Glutatión Transferasa/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de Riesgo , Fumar/efectos adversosRESUMEN
A case-control study involving 750 cases with squamous-cell carcinoma of the head and neck (HNSCC) and an equal number of healthy controls was initiated to investigate the association of polymorphisms in the drug metabolizing genes cytochrome P450 1A1 (CYP1A1), CYP1B1, CYP2E1 and glutathione S-transferase M1 (GSTM1) with the risk of developing cancer. Attempts were also made to identify the role and nature of gene-gene and gene-environment interactions in modifying the susceptibility to HNSCC. Polymorphisms in drug metabolizing CYPs or GSTM1 showed modest associations with cancer risk. However, cases carrying haplotypes with variant alleles of both CYP1A1*2A and *2C or CYP1B1*2 and *3 or CYP2E1*5B and *6 were at significant risk of developing HNSCC. Likewise, cases carrying a combination of variant genotypes of CYPs and GSM1 (null) were at higher risk (up to 5-fold) of developing HNSCC. HNSCC risk also increased several-fold in cases carrying variant genotypes of CYPs who were regular tobacco smokers (8-18-fold), tobacco chewers (3-7-fold), or alcohol users (2-4-fold). Statistical analysis revealed a more than multiplicative interaction between combinations of the variant genotypes of CYPs and GSTM1 (null) and between variant genotypes and tobacco smoking or chewing or alcohol consumption, in both case-control and case-only designs. The data thus suggest that although polymorphisms in carcinogen-metabolizing CYPs may be a modest risk factor for developing HNSCC, gene-gene, and gene-environment interactions play a significant role in modifying the susceptibility to HNSCC.
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Carcinoma de Células Escamosas/genética , Sistema Enzimático del Citocromo P-450/genética , Epistasis Genética , Interacción Gen-Ambiente , Glutatión Transferasa/genética , Neoplasias de Cabeza y Cuello/genética , Adulto , Consumo de Bebidas Alcohólicas/efectos adversos , Sustitución de Aminoácidos , Carcinoma de Células Escamosas/enzimología , Estudios de Casos y Controles , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/enzimología , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Análisis de Secuencia de ADN , Uso de Tabaco/efectos adversosRESUMEN
The present case-control study involving 750 cases and equal number of healthy controls investigates the association of polymorphism in cytochrome P450 2C9 (CYP2C9) with head and neck squamous cell carcinoma (HNSCC) and response in patients receiving chemotherapy or combination of radio-chemotherapy. The frequency of heterozygous or homozygous genotypes of CYP2C9*2 & CYP2C9*3, which leads to the poor metabolizer (PM) genotype was significantly higher in HNSCC cases when compared to the healthy controls resulting in significantly increased risk in the cases. Tobacco use in the form of tobacco smoking or tobacco chewing was found to increase the risk several fold in cases when compared to the non-tobacco users. Likewise, alcohol intake in cases with variant genotypes of CYP2C9*2 or CYP2C9*3 also significantly increased the HNSCC risk in cases when compared to non-alcohol users. Further, majority of the cases carrying variant alleles of both CYP2C9*2 or CYP2C9*3 were found to respond poorly to the chemotherapy or combination of radio-chemotherapy. The data suggests a significant association of the CYP2C9 polymorphism with HNSCC and treatment outcome.
RESUMEN
AIM: Chemo-radiotherapy (CRT) is the standard of care for treating almost all cervical carcinoma patients on the basis of the National Cancer Institute (NCI) alert. The disease burden in developing countries is more advanced with poor general condition than in patients in the trials prompting the NCI alert. Therefore, practicing CRT as standard of care should be tested in these patients. METHODS: A randomized controlled trial was conducted comparing radiotherapy (RT) alone with CRT (cisplatin 40 mg/m(2) weekly × 5) in patients with localized stage Ib to IVa cervical carcinoma between September 2006 and December 2008. External beam RT was delivered using a telecobalt unit. This was followed by 12-18 Gy of brachytherapy. RESULTS: In total, 305 patients were recruited: RT alone (150) and CRT (155). The median follow up was 34 months. Locoregional relapse-free survival (LRFS) at 2 years was 55 and 54% for the RT and CRT group, respectively, with a median LRFS time of 27 and 30 months for the RT and CRT group, respectively, (P = 0.624). Overall survival (OS) at 2 years was 58 and 60%, with a median OS of 31 and 34 months for the RT and CRT group, respectively; (P = 0.9). The toxicity profile, both acute and late, were comparable in both groups; CONCLUSION: No improvement in outcome was seen with addition of cisplatin. In the Indian subcontinent where patients present at late stages with poor general condition and limited access to good supportive care, RT alone still remains a valid option.
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Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Adulto , Braquiterapia , Quimioradioterapia , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias del Cuello Uterino/patología , Adulto JovenRESUMEN
The causes of lung cancer might be many, but genetic variation in the genes of carcinogen-metabolizing enzymes, tumor suppressor proteins, and/or DNA-repairing enzymes can also play a significant role in lung cancer susceptibility. The tumor suppressor protein p53 functions to induce cell cycle arrest, DNA repair, or apoptosis. Polymorphism in its gene can, therefore, play a significant role in cancer susceptibility. Present report evaluated the association of polymorphism in exon 4 Arg72Pro (G>C) of the p53 gene with lung cancer susceptibility using 175 cancer cases and 202 controls from the North Indian population. Binary logistic regression analysis revealed that the Pro72Pro genotype was significantly associated with increasing risk for lung cancer in younger age patients (≤55 years) (adjusted odds ratio [OR]=2.72, 95% confidence intervals [95% CI] 0.99-7.85, p<0.05). Histological stratification of lung cancer revealed that the Pro72Pro genotype was associated with higher risk for squamous cell carcinoma (OR=3.05, 95% CI 1.07-8.87, p<0.05). Genetic variation Arg72Pro of the p53 gene may contribute to higher risk of SCC of lung in the North Indian population.
Asunto(s)
Carcinoma de Células Escamosas/genética , Genes p53/genética , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple/fisiología , Anciano , Sustitución de Aminoácidos/genética , Sustitución de Aminoácidos/fisiología , Arginina/genética , Pueblo Asiatico/genética , Pueblo Asiatico/estadística & datos numéricos , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/etnología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/genética , Genética de Población , Genotipo , Humanos , India/epidemiología , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etnología , Masculino , Persona de Mediana Edad , Prolina/genéticaRESUMEN
1. The present study aimed to identify the expression of carcinogen metabolizing cytochrome P4502A (CYP2A) isoenzymes in freshly prepared rat peripheral blood lymphocytes (PBL) isolated from adult rats and investigate similarities in the regulation of lymphocyte CYP2A-isoenzymes with the tissue enzyme. 2. qRT-PCR studies demonstrated significant constitutive mRNA expression of CYP2A-isoenzymes in PBL isolated from male and female rats which further increases significantly after pretreatment with nicotine or 3-methylcholanthrene (MC) indicating responsiveness of CYP2A-isoenzymes in PBL. This increase in the CYP2A expression was associated with an increase in the protein expression and CYP2A3-dependent coumarin hydroxylase (COH) activity in PBL. 3. Clinical studies further demonstrated significant increase in the expression of CYP2A6 and associated enzyme activity in PBL isolated from lung cancer patients. Our data thus provided evidence for similarities in the regulation of carcinogen metabolizing CYP2A-isoenzymes in PBL with the tissue enzymes. Further, responsiveness of blood CYP2A6 in human blood lymphocytes isolated from lung cancer patients has led us to suggest that associating expression profiles of CYP2A6 and other polycyclic aromatic hydrocarbons (PAH)-responsive CYPs in PBL with the genotyping data could lead to the development of a possible screen to monitor and predict environment-induced diseases and toxicity in humans.
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Hidrocarburo de Aril Hidroxilasas/sangre , Linfocitos/enzimología , Animales , Hidrocarburo de Aril Hidroxilasas/genética , Biomarcadores/sangre , Western Blotting , Separación Celular , Inhibidores Enzimáticos/farmacología , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Isoenzimas/sangre , Isoenzimas/genética , Cinética , Linfocitos/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: In developing countries especially in south Asia, there are growing habits of consumption of tobacco and its products in various forms. These are known to generate a strong free radical environment and when the free radicals overwhelm the antioxidant system, they may lead to degeneration of cellular components and mutations. AIM: The aim of this study is to assess the levels of oxidative stress determinants, which may be one of the critical factors in head and neck cancer development. MATERIALS AND METHODS: This study included 100 consenting SCCHN patients and 90 matched healthy controls and we assessed the total antioxidant capacity (TAC), glutathione (GSH), free radicals (RNS, ROS) and oxidative DNA adduct (8-OHdG). RESULTS: We observed a substantial rise in reactive oxygen species (ROS, ~3.0-fold) and reactive nitrogen species (RNS, ~1.7-fold), together with significant lowering in TAC (~1.2-fold) and GSH (~1.7-fold) was observed. The 8-OHdG levels were also found to be significantly (P < 0.05) higher in patients in comparison to controls. Pearson's correlation between blood ROS and GSH were found to be negatively correlated -0.38 (P < 0.01) and RNS and DNA damage positively correlated 0.44 (P < 0.01). CONCLUSION: Our present results demonstrate significant Redox imbalance in cancer patients suggesting their paramount importance in the development of SCCHN. The 8-OHdG could be the potential biomarker for evaluating risk of SCCHN. To develop new approaches of SCCHN prevention, there is a need of detailed study and better understanding of the molecular mechanisms underlying oxidative stress and DNA damage.
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Carcinoma de Células Escamosas/sangre , Daño del ADN , Desoxiguanosina/análogos & derivados , Neoplasias de Cabeza y Cuello/sangre , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Anciano , Antioxidantes/metabolismo , Carcinoma de Células Escamosas/genética , Estudios de Casos y Controles , Desoxiguanosina/sangre , Glutatión/sangre , Neoplasias de Cabeza y Cuello/genética , Humanos , Persona de Mediana Edad , Oxidantes/sangre , Oxidación-Reducción , Estrés Oxidativo , Especies de Nitrógeno Reactivo/sangre , Especies Reactivas de Oxígeno/sangre , Adulto JovenRESUMEN
The study investigates the association of polymorphism in glutathione S-transferases (GSTs) with susceptibility for head and neck squamous cell carcinoma (HNSCC) and its sites as well as treatment response in cases receiving chemotherapy (CT) and combination of CT-radiotherapy (CT-RT). The case-control study included 500 male cases and an equal number of healthy male controls. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the association between genotypes and cancer risk. An increase in the risk for HNSCC and cancers of oral cavity, larynx or pharynx was observed in cases with null genotypes of GSTM1 or GSTT1. The interaction of alcohol or tobacco with variant genotypes of GSTM1 or GSTT1 also resulted in a significant increase in the risk for HNSCC. Further, HNSCC cases carrying the null genotypes of GSTM1 and GSTT1 or variant genotypes of GSTP1 showed a significant and superior treatment response. The present data thus provides evidence for the association of polymorphisms in GSTs with risk for HNSCC and its treatment response.
Asunto(s)
Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/genética , Polimorfismo Genético , Consumo de Bebidas Alcohólicas/genética , Estudios de Casos y Controles , Demografía , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Fumar/genética , Tabaco sin Humo , Resultado del TratamientoRESUMEN
Distribution and gene-environment interaction of EPHX1 polymorphism was evaluated in 175 lung cancer patients and 322 controls from north India. Two novel non-synonymous, Lys117Arg and Leu263Phe, and twelve single nucleotide polymorphisms were identified in the present study. Binary logistic regression analysis showed association of polymorphism Tyr113His with increased risk of lung cancer (OR = 2.2, 95% CI = 1.2-4.0, p < .05). Gene-environment interaction revealed that patients with His113His and smoking habit had significantly greater risk of lung cancer (OR = 4.52, 95% CI = 0.93-43.05, p < .05). Present study provided evidence that EPHX1 polymorphism is associated with lung cancer susceptibility in Indian population.
Asunto(s)
Epóxido Hidrolasas/genética , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Polimorfismo Genético , Adulto , Anciano , Femenino , Humanos , India , Modelos Logísticos , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Fumar/efectos adversosRESUMEN
Protein-protein interactions play an important role in regulating the expression of huntingtin protein (htt). Expansion of polyglutamine tracts in htt results in neurodegenerative Huntington disease. Huntingtin interacting protein (HIP14) is an important interacting partner of htt and the altered interactions have been proposed to play an important role in disease progression. In the present study, an attempt has been made to explore the potential of several known Huntington inhibitors to inhibit HIP14. The docking studies have resulted in the identification of a novel binding site for these inhibitors distinct from the previously known ankyrin repeat domain. The results have been validated using geometry based docking transformations against the other binding pocket. The specificity of binding has been determined with high values of both accuracy and precision. Nine potential inhibitors obtained after screening belong to three distinct classes of compounds viz, carbohydrates (deoxy-glucose), alcohols (including phenolic scaffold) and tetracycline. The compounds form stable complex with protein exhibiting optimal intermolecular and Gibbs free energy. The hydrogen bonding and hydrophobic interactions predominantly contribute to the stability of these complexes. The present study identifies metoprolol, minocyclines and 18 F fluorodeoxyglucose as the best inhibitors that bind specifically to the new site. Therefore, these compounds can further be exploited for their potential to serve in the diagnosis and treatment of Huntington disease. The quantitative predictions provide a scope for experimental testing in future.
Asunto(s)
Aciltransferasas/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Inhibidores Enzimáticos/metabolismo , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/tratamiento farmacológico , Modelos Moleculares , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Aciltransferasas/química , Aciltransferasas/genética , Aciltransferasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Sitios de Unión , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Fluorodesoxiglucosa F18/química , Fluorodesoxiglucosa F18/metabolismo , Fluorodesoxiglucosa F18/farmacología , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Enlace de Hidrógeno , Metoprolol/química , Metoprolol/metabolismo , Metoprolol/farmacología , Minociclina/química , Minociclina/metabolismo , Minociclina/farmacología , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Péptidos/química , Péptidos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Tetraciclina/química , Tetraciclina/metabolismo , Tetraciclina/farmacología , TermodinámicaRESUMEN
A total of 100 patients with stage III or IV head or neck cancer, a performance status of 0-1, and anemia with hemoglobin (Hb) < 10 g/dL at baseline who where to receive chemotherapy concomitantly or sequentially with radiotherapy were randomized to receive either epoetin beta 10,000 IU thrice weekly (TW) (n = 52) and oral iron starting 10-15 days before the start of treatment or epoetin beta 30,000 IU once weekly (OW) (n = 48) and oral iron before the start of treatment. The mean Hb in patients on the thrice weekly (11.96 g/dL) and once weekly (12.50 g/dL) dosing schedules increased significantly (p < 0.01) at the end of the treatment in comparison to respective baseline values of 9.38 g/dL and 9.41 g/dL; levels were 1.2-fold higher, which was significant (p < 0.01), for patients on the once weekly schedule. That said, there was significant improvement (p < 0.01) in mean linear analog scale assessment (LASA) scores for energy level (EL), ability to perform daily activities (AL), and overall quality of life (QOL) for patients on both dosing schedules but these improvements did not differ significantly between schedules (p > 0.05). The 2-year overall survival for patients on both dosing schedules did not differ significantly (p > 0.05). Epoetin beta therapy was found to be equally beneficial and well tolerated for patients on both thrice weekly and once weekly dosing schedules.
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Anemia/tratamiento farmacológico , Anemia/etiología , Eritropoyetina/uso terapéutico , Neoplasias de Cabeza y Cuello/complicaciones , Anciano , Relación Dosis-Respuesta a Droga , Eritropoyetina/administración & dosificación , Hemoglobinas/análisis , Humanos , Hierro/administración & dosificación , Hierro/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
Secondary prophylaxis with recombinant human granulocyte colony stimulating factor (G-CSF) is recommended where patients have experienced febrile neutropenia in an earlier chemotherapy cycle and for whom the maintenance of chemotherapy dose intensity is important; or where febrile neutropenia has not occurred but prolonged neutropenia is causing excessive dose delay or reduction, where maintenance of dose intensity is important. The objective of this study was to determine the efficacy and feasibility of G-CSF as secondary prophylaxis when used along with full dose moderately myelotoxic chemotherapy following a prior cycle with febrile-neutropenia. Fifty-two patients aged 22-75 years with febrile neutropenia that required intravenous antibiotics following moderately myelotoxic chemotherapy were included. These patients received the next cycle of the same chemotherapy regime without dose modification but with support of filgrastim 24 h after completion of chemotherapy (300 µg/day/subcutaneously (s.c.) for weight < 60 kg, 480 µg/day/s.c. for weight > 60 kg, for at least 10 consecutive days), patients in whom neutropenia was associated with a life-threatening infection and those who developed prolonged myelosuppression were excluded. The use of the hematopoietic growth factor G-CSF was shown to shorten the neutrophil recovery time, resulting in significant reduction of incidence of febrile neutropenia, hospitalization and use of broad spectrum antibiotics. There was no drug related death or adverse events associated with either cycle. In conclusion, recombinant human G-CSF is effective and relatively safe as a secondary prophylaxis with full dose chemotherapy in patients who develop febrile neutropenia following prior cycles of moderately myelotoxic chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fiebre/complicaciones , Factor Estimulante de Colonias de Granulocitos/farmacología , Neoplasias/tratamiento farmacológico , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológico , Adulto , Anciano , Análisis de Varianza , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Filgrastim , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Persona de Mediana Edad , Neutropenia/complicaciones , Proteínas RecombinantesRESUMEN
The present case-control study attempted to investigate the association of poor metabolizer (PM) genotypes of cytochrome P450 2D6 (CYP2D6*4 and CYP2D6*10) with squamous cell carcinoma of head and neck (HNSCC) and treatment response in patients receiving chemotherapy or combination of chemo- and radiotherapy. Cases with the PM genotypes of CYP2D6 displayed a significantly increased risk for HNSCC as compared to wild type genotypes. The risk was found to further increase in cases (up to 4.8) carrying combination of PM genotypes of CYP2D6, CYP2C9 (CYP2C9*2) or CYP2C19 (CYP2C19*2), suggesting that synergism amongst the PM genotypes of drug metabolizing CYPs leads to impairment in the detoxification of the tobacco carcinogens. A small increase in the risk in tobacco (chewers or smokers) or alcohol users in cases with CYP2D6*4 allele while no change or even a small decrease in risk in cases with CYP2D6*10 allele when compared to non-tobacco or alcohol users have suggested that CYP2D6 genotypes alone do not appear to interact significantly with environmental risk factors in modifying the susceptibility to HNSCC. Furthermore, most of the cases carrying PM genotypes of CYP2D6 did not respond to the treatment. Moreover, higher prevalence of non-responders among cases carrying combination of CYP2D6*4 or CYP2D6*4, CYP2C9*2 and CYP2C19*2 have demonstrated that interaction of PM genotypes may not only significantly modify the susceptibility to HNSCC but also the treatment response.
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Hidrocarburo de Aril Hidroxilasas/genética , Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP2D6/genética , Neoplasias de Cabeza y Cuello/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Estudios de Casos y Controles , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The present case-control study was carried out to investigate the association of functionally important polymorphisms of cytochrome P450 1A2 (CYP1A2) involved in the metabolic activation of tobacco derived procarcinogens with squamous cell carcinoma (SCC) of lung in North Indian men. The study consisted of 200 male cases with SCC of lung and an equal number of age and sex matched healthy controls. Our data showed that variant genotype of CYP1A2*1D and CYP1A2*1F were significantly associated with increased susceptibility to SCC of lung. Likewise, GSTM1 null genotype was found to be over represented in patients when compared to controls. Haplotype analysis revealed that haplotype, G-Tdel-T-C was significantly associated with risk to SCC of lung. Moreover, a significant increase in the risk to SCC of lung in the cases carrying combination of variant genotype of CYP1A2 with either CYP1A1 or GSTM1 have shown that gene-gene interactions may play an important role in squamous cell lung cancer risk. Our data also revealed that smokers or tobacco chewers carrying variant alleles of either CYP1A2*1D or CYP1A2*1F were at increased risk to SCC of lung, further demonstrating that CYP1A2 genotypes interact with environmental risk factors in enhancing the risk to squamous cell lung carcinoma.
Asunto(s)
Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A2/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético , Adulto , Alelos , Estudios de Casos y Controles , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
To develop blood lymphocyte cytochrome P450 1A1 (CYP1A1) expression as a surrogate for monitoring tissue expression for polycyclic aromatic hydrocarbon (PAH) induced toxicity, the present study attempted to characterize CYP1A1 mRNA expression and its associated catalytic activity in freshly prepared blood lymphocytes isolated from healthy controls and patients suffering from tobacco induced lung cancer. Human blood lymphocytes were found to express CYP1A1 mRNA and significant activity of 7-ethoxyresorufin-O-deethylase (EROD). Significant increase in the activity of EROD and CYP1A1 mRNA was observed in blood lymphocytes isolated from patients suffering from lung cancer. Further, controls with variant genotypes of CYP1A1 (Msp1 or Ile/Val polymorphism) exhibited significant increase in the enzyme activity associated with an increase in CYP1A1 mRNA expression when compared to the controls with wild type genotype. Patients with variant genotypes of CYP1A1 also exhibited much greater increase in the blood lymphocyte CYP1A1 mRNA expression and EROD activity when compared to controls or patients with wild type genotype. Our data thus provides evidence of CYP1A1 expression in freshly isolated blood lymphocytes and differences in reactivity in individuals with variant genotypes of CYP1A1, suggesting that blood lymphocyte CYP1A1 expression profile could help in identifying individuals at risk to environment induced lung cancer.
Asunto(s)
Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A1/genética , Neoplasias Pulmonares/genética , Linfocitos/enzimología , Citocromo P-450 CYP1A1/análisis , Citocromo P-450 CYP1A1/metabolismo , Expresión Génica , Genotipo , Humanos , Masculino , Polimorfismo Genético , ARN Mensajero/metabolismo , Fumar/efectos adversosRESUMEN
A case control study was undertaken to investigate the association of polymorphisms in cytochrome P4501A1 (CYP1A1) with squamous cell carcinoma of head and neck (HNSCC) in North Indian population. The variant genotypes of CYP1A1*2A and CYP1A1*2C were found to be overrepresented in cases when compared to controls. The HNSCC risk also increased several folds in cases with combination of variant genotypes of CYP1A1*2A or CYP1A1*2C with null genotype of glutathione-S-transferase M1 (GSTM1), a phase II enzyme, particularly in cases who were tobacco users (smokers and tobacco chewers), demonstrating the role of gene-gene and gene-environment interactions in the development of HNSCC.
Asunto(s)
Carcinoma de Células Escamosas/genética , Citocromo P-450 CYP1A1/genética , Neoplasias de Cabeza y Cuello/genética , Polimorfismo Genético , Adulto , Anciano , Carcinoma de Células Escamosas/enzimología , Estudios de Casos y Controles , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Neoplasias de Cabeza y Cuello/enzimología , Humanos , India , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Medición de Riesgo , Factores de Riesgo , Fumar/efectos adversos , Tabaco sin Humo/efectos adversosRESUMEN
A case control study was carried out to investigate the association of functionally important polymorphism in cytochrome P450 2A6 (CYP2A6) and glutathione S-transferase P1 (GSTP1) genes with head and neck squamous cell carcinoma (HNSCC) and treatment response in cases receiving a combination of chemo-radiotherapy. The study group consisted of 350 males suffering from HNSCC and an equal number of male controls. Multivariate logistic regression analysis revealed statistically significant decrease in risk to HNSCC in cases with variant genotypes (CYP2A6*1B and CYP2A6*4C) of CYP2A6 (OR: 0.78; 95% CI: 0.43-1.22; P=0.04) or GSTP1 (OR: 0.71; 95% CI: 0.51-1.00; P=0.05). The risk associated with these variant genotypes was found to be further decreased in cases carrying a combination of variant genotypes of CYP2A6 and GSTP1 (OR: 0.40; 95% CI: 0.25-0.65; P=0.00). A similar decrease in risk was observed in cases with variant genotypes of CYP2A6 (OR: 0.59; 95% CI: 0.40-0.86; P=0.00) or GSTP1 (OR: 0.62; 95% CI: 0.42-0.91; P=0.01) and who were regular tobacco users (cigarette smokers or tobacco chewers). Interestingly, only 27% of the cases carrying the variant forms of CYP2A6 (*1A/*4C+*1B/*4C+*4C/*4C) responded to the treatment for HNSCC when compared to those with wild-type genotype (69%). However with GSTP1, cases with homozygous mutant genotype (Val/Val) showed a superior treatment response (75%) when compared to cases with wild-type genotype (25%). Further, cases carrying a combination of variant genotype of CYP2A6 and wild-type genotype of GSTP1 exhibited a very poor treatment response demonstrating that polymorphisms in CYP2A6 and GSTP1 not only modified the risk to HNSCC but also played a major role in determining the chemotherapeutic response.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Gutatión-S-Transferasa pi/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/terapia , Polimorfismo Genético/genética , Carcinoma de Células Escamosas/secundario , Estudios de Casos y Controles , Terapia Combinada , Citocromo P-450 CYP2A6 , Genotipo , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Fumar , Resultado del TratamientoRESUMEN
The present case-control study investigates the association of polymorphisms in cytochrome P450 2E1 (CYP2E1), involved in the metabolism of tobacco carcinogens and alcohol, with Head and Neck Squamous Cell Carcinoma (HNSCC). In addition, the interaction of CYP2E1 (CYP2E1*5B and CYP2E1*6) with other genetic factors (null genotype of glutathione-S-Transferase M1, GSTM1, X-Ray Repair Cross Complementing Group I, XRCC1 (Arg194Trp), and environmental risk factors such as alcohol and tobacco in modifying HNSCC risk were investigated. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a total of 350 male cases of HNSCC and an equal number of healthy male controls. Statistical analysis showed a significant increase in HNSCC risk in cases with variant genotypes of CYP2E1*5B (RsaI) (O.R. 3.44; 95% C.I. 1.45-8.14) and CYP2E1*6 (DraI) (O.R. 1.76; 95% C.I. 1.28-2.41). Haplotype analysis revealed that haplotype T-A was associated with a greater than 10-fold increase in risk for HNSCC. Our data also revealed a several fold increase in HNSCC risk in cases carrying a combination of variant genotypes of CYP2E1 with the null genotype of GSTM1 or XRCC1 variant genotypes. Alcohol or tobacco use (both smoking and chewing) were also found to interact with variant genotypes of CYP2E1 in significantly enhancing HNSCC risk. This increase in risk associated with an interaction of CYP2E1 genotypes with GSTM1 or XRCC1 or with tobacco and alcohol use demonstrates the importance of gene-gene and gene-environment interactions in the development of HNSCC.