RESUMEN
Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme in the catabolism of 5-fluorouracil (5-FU). It has been reported from various laboratories that the plasma concentration of 5-FU was influenced by DPD activities in various normal human organs (e.g. liver or lymphocytes). Since the congenital deficiency in DPD caused severe, in some cases lethal, FU-related toxicity, it was decided to collect data about the DPD activity in colorectal cancer patients in order to investigate the possible correlation between the enzyme activity and appearance of the side effects of 5-FU. Assuming that DPD activity in lymphocytes represents the 5-FU catabolic capacity of the organism, DPD activity was determined in the lymphocytes of 48 patients with colorectal cancer after surgery during the therapeutic course with 5-FU and folinic acid. On the basis of the enzyme activity, patients were divided into three categories: low (DPD <5.03 pmol/min/10(6) lymphocytes); medium (DPD = 5.04-13.25 pmol/min/10(6) lymphocytes), and high (DPD > 13.26 pmol/min/10(6) lymphocytes) activity groups. By evaluating the toxic side effects during the 5-FU + folinic acid treatment, the following results were obtained. In the low DPD activity group, 9 of 11 patients had 5-FU-related side effects (mucositis, diarrhea, myelotoxicity, angina pectoris, hypertension). In 3 patients, no change of the therapy was needed, in 3 patients symptoms could be reversed by dose reduction of 5-FU while in 3 patients interruption of 5-FU therapy was needed. In the medium DPD activity group, mild toxicity (diarrhea, transitory hypertension) occurred in 5 of 29 and in the high activity group (diarrhea) in 1 of 8 patients, respectively. In these last two groups, no dose reduction of 5-FU was necessary. The present study furnished further evidence for the possible correlation between the 5-FU side effects and DPD function. Consequently, it is recommended to measure DPD activity prior to 5-FU based chemotherapy, which might be helpful in avoiding drug-related toxicity by adjusting the dose of 5-FU individually.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/efectos adversos , Oxidorreductasas/metabolismo , Adulto , Anciano , Neoplasias Colorrectales/enzimología , Dihidrouracilo Deshidrogenasa (NADP) , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In the chemotherapy of colorectal cancers the most frequently given drug is 5-fluorouracil, which in certain cases reduces or delays the appearance of the local recurrence or metastasis. It is well known that the patient's response to 5-fluorouracil is very different concerning both, effects and side effects. More than 80% of the infused drug is catabolised in the first 20 minutes after the treatment. The first and rate limiting enzyme of the catabolism is dihydropyrimidine dehydrogenase, which has the highest activity in the liver and lymphocytes. The activity of this enzyme shows correlation with the blood level of 5-fluorouracil. The deficiency of this enzyme caused severe, in some cases lethal toxicity, its congenital deficiency is responsible for familial pyrimidinaemia. Authors intended to collect data about the dihydropyrimidine dehydrogenase activity of colorectal cancer patients, in order to screen enzyme deficiency or very low enzyme activity, which might be in connection with the appearance of severe side effects, moreover to determine the optimal dose of 5-fluorouracil before the treatment. Dihydropyrimidine dehydrogenase activity was determined in the lymphocytes of 48 colorectal cancer patients, treated by 5-fluorouracil, at the beginning of each cytostatic cycle. The enzyme activity of the patients was between 1.2 and 24.4 pmol/min/10(6) lymphocyte. The value of the enzyme activity fluctuated in a range, characteristic for the individual patients and this value was not modified by the 5-fluorouracil treatment. Dividing the patients in two groups, low (lower than 5 pmol/min 10(6) lymphocyte) and high (higher than 15 pmol/min 10(6) lymphocyte) dihydropirimidine dehydrogenase activity, we found that decrease in the white blood cell number and appearance of the side effects occurred with much higher frequency in the low activity group which resulted in the reduction of the dose or in more serious cases interruption of the treatment. Authors conclude that the determination of the dihydropyrimidine dehydrogenase activity in the lymphocytes is a valuable method in the prediction of the toxic side effects of 5-fluorouracil, in the screening of the congenital enzyme deficiency and in the individualization of the 5-fluorouracil dosage.
Asunto(s)
Antimetabolitos Antineoplásicos/toxicidad , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/toxicidad , Oxidorreductasas/análisis , Adyuvantes Farmacéuticos/uso terapéutico , Adulto , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/enzimología , Dihidrouracilo Deshidrogenasa (NADP) , Femenino , Fluorouracilo/uso terapéutico , Humanos , Hígado/enzimología , Linfocitos/enzimología , Masculino , Persona de Mediana EdadRESUMEN
Merkel cell cancer is a rare carcinoma arising from the neuroendocrin cells of the skin. The diagnosis is based on the clinical behaviour, histopathologic and ultrastructural findings and immunohistochemical results. An unusual case of Merkel cell carcinoma is presented. Mass from the umbiculus and a right inguinal lymph node was excised in a 63-year-old female. The histologic features of a typical, primitive small cell tumor combined with the immunohistochemical evaluations established the diagnosis. Rare polynuclear giant cells were focally present in our case. Patient was treated with combination of chemotherapy (Cisplatin, Etoposid) and radiotherapy. Control examinations showed complete respond. One year later metastasis developed. Resection of all known metastasis were performed. Two months after the laparotomy she died of metastatic disease. The autopsy did not reveal any other primary tumor. The capricious nature of the clinical course and the differences between this tumor and other carcinomas is emphasized.