RESUMO
BACKGROUND: Chronotherapy is one of the several approaches to increase efficacy and reduce toxicity of chemotherapy. In a phase II study in the second-line in patients with metastatic colorectal cancer (mCRC), we found that chronomodulated XELOX (XELOX(30Chron)) was a well-tolerated regimen with potentially reduced toxicity. PATIENTS AND METHODS: One hundred and forty-one patients with unresectable mCRC were enrolled in a randomized study comparing standard XELOX (XELOX(30)), arm A, and XELOX(30Chron), arm B-both with short-time infusion of oxaliplatin-with the primary aim of reducing overall toxicity. RESULTS: Overall toxicity grade 2-4 was 90% versus 85%, P = 0.47 and grade 3-4 was 31% versus 37%, P = 0.6 in arm A and B, respectively. We found no significant differences in median overall survival (17.6 versus 15.5 months; P = 0.068) and median progression-free survival (8.9 versus 8.8 months; P = 0.7). The incidence of grade 3 neuropathy was 16% in arm A and 19% in arm B (P = 0.7) after a cumulative dose of oxaliplatin of 1000 mg/m(2). CONCLUSION: XELOX(30Chron) does not reduce toxicity or improve efficacy. A 30-min infusion of oxaliplatin is safe and does not increase the severity of chronic neuropathy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Cronofarmacoterapia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , OxaloacetatosRESUMO
This study investigated the relationship between the dihydrouracil/uracil (UH(2)/U) plasma ratio, a surrogate marker of dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU)-related early toxicity. Plasma UH(2)/U ratios were determined in 68 colorectal cancer patients and 100 healthy controls. A cut-off value indicative of DPD deficiency was calculated using receiver operator characteristics. Patients experiencing toxicity were screened for the DPD G-to-A point mutation within the 5'-splicing donor site of intron 14 (IVS14+1G>A). Overall, 24/68 patients (35%) experienced toxicity (all grades) and abnormal UH(2)/U ratios were demonstrated in 21/24 (87.5%) patients. Drug concentrations up to 130 times the recommended level were found in 13/24 (54%) patients experiencing toxicity. One patient experiencing toxicity was a heterozygous carrier of the IVS14+1G>A mutation. A low UH(2)/U plasma ratio had a sensitivity of 0.87 and specificity of 0.93 for predicting 5-FU-induced toxicity. Systematic detection of DPD-deficient patients using the UH(2)/U ratio could optimize 5-FU-based chemotherapy and minimize life-threatening toxicity.
Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Uracila/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Análise Mutacional de DNA , Di-Hidrouracila Desidrogenase (NADP)/genética , Feminino , Fluoruracila/sangue , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Sítios de Splice de RNA/genética , Uracila/sangueRESUMO
Adverse drug reactions to 5-fluorouracil (5-FU)-based chemotherapy have been reported to be due, in part, to genetic variants of the genes for the drug-related enzymes thymidylate synthase (TS; TYMS gene), methylenetetrahydrofolate reductase (MTHFR gene) and dihydropyrimidine dehydrogenase (DPD; DPYD gene). This study investigated whether selected genetic variants of the TYMS, MTHFR and DPYD genes predict 5-FU-related early toxicity. The prevalence of the genetic variants was determined in 122 colorectal cancer patients and in a reference population of 320 blood donors. Subgroup analysis of 68 of the colorectal cancer patients was carried out to determine the relationship between selected gene variants detected in peripheral mono nuclear cells and tolerability during the first or second cycle of 5-FU based treatment. Toxicity was linked to the TYMS 2R/2R variant (relative risk [RR] 1.66; sensitivity 0.37; specificity 0.77) and to the MTHFR c1298 C/C genetic variant (RR 1.77; sensitivity 0.17; specificity 0.91). Patients with the genetic variant IVS14+1 G/A or c1896 C/T in the DPYD gene had a statistically significant increased risk of experiencing toxicity (RR 2 and 6, respectively), both having a high specificity (0.97 and 0.98, respectively) and low sensitivity (0.04 and 0.13, respectively). It is concluded that pre-treatment detection of genetic variants can help to predict early toxicity experienced by patients receiving 5-FU-based chemotherapy.
Assuntos
Adenocarcinoma/enzimologia , Antimetabólitos Antineoplásicos/toxicidade , Neoplasias Colorretais/enzimologia , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/toxicidade , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Timidilato Sintase/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , Timidilato Sintase/metabolismoRESUMO
This study was designed to compare thymidylate synthase (TS) genotype, mRNA and protein levels in primary colorectal adenocarcinoma, and to examine the correlation between microsatellite instability (MSI) and TS expression. The TS genotype of 68 patients with colorectal cancer was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis in peripheral blood mononuclear cells and tumour tissue. The TS mRNA levels in tumour tissue were measured by reverse-transcription PCR, and TS protein levels and MSI status were assessed using immunohistochemistry. Significantly higher mRNA and protein levels were observed in patients with the TS 3R/3R versus the 2R/2R and 2R/3R genotypes. There was no correlation between TS single nucleotide polymorphism and TS expression. Individuals homozygous for the six base-pair insertion in the 3'-untranslated region had significantly higher TS mRNA levels than heterozygous and homozygous wild type individuals. The TS mRNA and protein levels were significantly higher in microsatellite unstable tumours compared with microsatellite stable tumours. There was a significant association between the number of TS enhancer region repeats (in blood) and intratumoural TS mRNA and protein levels. A larger case series investigating the role of TS gene polymorphisms as predictors of sensitivity to 5-fluorouracil-based chemotherapy is required.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Polimorfismo Genético/genética , Timidilato Sintase/genética , Timidilato Sintase/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Feminino , Fluoruracila/uso terapêutico , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The activities of the enzymes cytidine deaminase (CDD), deoxycytidine kinase (dCK), adenosine deaminase (ADA), and purine nucleoside phosphorylase (PNP), have been investigated in the promyelocytic leukemia cell line HL60. The activities of the enzymes corresponded well with that seen in acute myeloid leukemia cells except, that the CDD activity was very low in the HL60 cells. Induction of differentiation in HL60 cells by 1,25 dihydroxy D3 resulted in an increase in CDD from 12 to 247 nmol/h/mg and a decrease in ADA from 1326 to 896 nmol/h/mg, while the activities of dCK, and PNP were unchanged. Retinoic acid, another used inducer of differentiation, gave no changes of the enzyme activities. The increase in CDD activity induced by 1,25 dihydroxy D3 was prevented by inhibition of protein synthesis, whereas inhibition of proliferation of the cells did not abolish the increase of CDD. The changes correspond well with the differences seen between immature and mature myeloid cells. The results may have consequences for the interpretation of results obtained with cytostatics, which are metabolized by the enzymes.
Assuntos
Calcitriol/farmacologia , Citidina Desaminase/metabolismo , Nucleosídeo Desaminases/metabolismo , Células Tumorais Cultivadas/enzimologia , Diferenciação Celular/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/patologiaRESUMO
Deoxycytidine kinase (dCK) is important in the 5'-phosphorylation of deoxynucleoside analogs. Like dCK, thymidine kinase 2 (TK2) catalyzes the initial step of the phosphorylation of dcyd to dCTP. Thymidine is a strong inhibitor of the dCK activity of TK2. We examined the ratio of the dcyd phosphorylation carried out by dCK and by TK2 (dCK/TK2-dcyd) in lymphocytes from CLL patients and from donors. In the CLL lymphocytes we found a 3.5-fold average increase. Therefore, we conclude that addition of thymidine in the treatment of CLL with deoxynucleoside analogs will not be of any advantage. Furthermore, our results can explain earlier findings in CML and AML lymphocytes where the ara-C phosphorylation was twice the dcyd phosphorylation.
Assuntos
Desoxicitidina Quinase/metabolismo , Leucemia Linfocítica Crônica de Células B/enzimologia , Linfócitos/enzimologia , Timidina Quinase/metabolismo , Células Cultivadas , Cladribina/metabolismo , Humanos , Fosforilação , Especificidade por Substrato , Células Tumorais CultivadasRESUMO
A case of visceral leishmaniasis in a 39-year-old woman is presented. It is the first case in Denmark, in an otherwise healthy person. The patient was infected on a short holiday in Malta.
Assuntos
Leishmaniose Visceral , Adulto , Dinamarca/epidemiologia , Feminino , Humanos , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/imunologia , Malta , ViagemAssuntos
Adenosina Desaminase/sangue , Leucemia Mieloide Aguda/enzimologia , Nucleosídeo Desaminases/sangue , Pentosiltransferases/sangue , Purina-Núcleosídeo Fosforilase/sangue , Adulto , Idoso , Feminino , Humanos , Leucemia/enzimologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Contagem de Leucócitos , Leucócitos/enzimologia , Masculino , Pessoa de Meia-IdadeAssuntos
Sobrevivência Celular/efeitos dos fármacos , Citarabina/farmacologia , Nucleosídeos/farmacologia , Linhagem Celular , Citidina/farmacologia , Desoxiadenosinas/farmacologia , Desoxicitidina/farmacologia , Desoxiguanosina/farmacologia , Interações Medicamentosas , Humanos , Cinética , Leucemia Promielocítica Aguda , Tetra-Hidrouridina/farmacologia , Uridina/farmacologiaAssuntos
Carcinoma Broncogênico/enzimologia , Granulócitos/enzimologia , Neoplasias Pulmonares/enzimologia , Linfócitos/enzimologia , Purinas/metabolismo , Adenina Fosforribosiltransferase/sangue , Adenosina Desaminase/sangue , Adenosina Quinase/sangue , Adulto , Idoso , Feminino , Humanos , Hipoxantina Fosforribosiltransferase/sangue , Masculino , Pessoa de Meia-Idade , Nucleotidases/sangue , Purina-Núcleosídeo Fosforilase/sangueAssuntos
2',5'-Oligoadenilato Sintetase/metabolismo , Herpes Zoster/enzimologia , Interferon Tipo I/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Adolescente , Adulto , Idoso , Carcinoma Broncogênico/enzimologia , Carcinoma Broncogênico/terapia , Feminino , Herpes Zoster/terapia , Humanos , Leucócitos/enzimologia , Linfoma/enzimologia , Masculino , Pessoa de Meia-Idade , Fatores de TempoAssuntos
Citarabina/toxicidade , Citidina Desaminase/metabolismo , Citidina/farmacologia , Desoxicitidina Quinase/metabolismo , Desoxicitidina/farmacologia , Leucemia Promielocítica Aguda/metabolismo , Nucleosídeo Desaminases/metabolismo , Fosfotransferases/metabolismo , Medula Óssea/enzimologia , Células da Medula Óssea , Divisão Celular/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/patologia , Tetra-Hidrouridina/farmacologia , Tretinoína/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismoAssuntos
Desoxicitidina Quinase/sangue , Leucemia Linfocítica Crônica de Células B/enzimologia , Linfócitos/enzimologia , Timidina Quinase/sangue , Cromatografia em Gel , Cromatografia por Troca Iônica , Desoxicitidina Quinase/isolamento & purificação , Humanos , Isoenzimas/sangue , Isoenzimas/isolamento & purificação , Leucemia Linfocítica Crônica de Células B/sangue , Valores de Referência , Timidina Quinase/isolamento & purificaçãoAssuntos
5'-Nucleotidase/sangue , Adenosina Desaminase/sangue , Doenças do Sistema Imunitário/enzimologia , Leucócitos Mononucleares/enzimologia , Nucleosídeo Desaminases/sangue , Pentosiltransferases/sangue , Purina-Núcleosídeo Fosforilase/sangue , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Lactente , Ativação Linfocitária/fisiologia , Masculino , Pessoa de Meia-IdadeAssuntos
Adenosina Desaminase/sangue , Mononucleose Infecciosa/enzimologia , Transtornos Mieloproliferativos/enzimologia , Nucleosídeo Desaminases/sangue , Nucleotidases/sangue , Pentosiltransferases/sangue , Purina-Núcleosídeo Fosforilase/sangue , 5'-Nucleotidase , Ensaios Enzimáticos Clínicos , Humanos , Mononucleose Infecciosa/diagnóstico , Transtornos Mieloproliferativos/diagnósticoAssuntos
Hipertireoidismo/sangue , Mixedema/sangue , Hormônio Liberador de Tireotropina , Tireotropina/sangue , Adulto , Idoso , Estudos de Avaliação como Assunto , Feminino , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Testes de Função Tireóidea , Fatores de Tempo , Tri-Iodotironina/sangueAssuntos
Bebidas Alcoólicas , Vinho , Bebidas Alcoólicas/análise , Alcoolismo , Dinamarca , Etanol/análise , Humanos , Vinho/análiseRESUMO
Initial phosphorylation and deamination of cytosine arabinoside (Ara-C) and the natural metabolite deoxycytidine (CdR) were estimated in cell free extracts of leucocytes from patients with CML and controls. Phosphorylation of CdR had been increased while deamination of CdR in extracts of CML cells from peripheral blood had been decreased compared with normal leucocytes. Comparing the ratios between Ara-C and CdR phosphorylation it was revealed that these were twice as high in CML cells as in normal leucocytes, whereas no difference was found when comparing ratios between Ara-C and CdR deamination. From these discoveries it is proposed that Ara-C can be combined with CdR with advantage, because apparently CdR protects the normal cells more than the malignant ones.
Assuntos
Citarabina/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Leucócitos/enzimologia , Adulto , Idoso , Citarabina/sangue , Citidina Desaminase/sangue , Desaminação , Desoxicitidina Quinase/sangue , Feminino , Humanos , Leucemia Mieloide/enzimologia , Masculino , Pessoa de Meia-Idade , FosforilaçãoRESUMO
Initial phosphorylation and deamination of cytosine arabinoside (Ara-C) and the natural metabolite deoxycytidine (CdR) were estimated in cell free extracts of leucocytes from patients with CML and controls, Phosphorylation of CdR had been increased while deamination of Cdr in extracts of CML cells from peripheral blood had been decreased compared with normal leucocytes. Comparing the ratios between Ara-C and CdR phosphorylation it was revealed that these were twice as high in CML cells as in normal leucocytes, whereas no difference was found when comparing ratios between Ara-C and CdR deamination. From these discoveries it is proposed that Ara-C can be combined with CdR with advantage, because apparently CdR protects the normal cells more than the malignant ones.