RESUMEN
BACKGROUND: Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective). PATIENTS AND METHODS: Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2). On days 4-10, patients received regorafenib 160 mg orally once daily. RESULTS: The median duration of treatment was 108 (range 2-345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥ 3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand-foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42-281 days). CONCLUSION: Regorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Neoplasias Colorrectales/metabolismo , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Humanos , Leucovorina/administración & dosificación , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacocinética , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
The introduction of VP-16 into high-dose therapy regimens used for conditioning before BMT or PBSCT has resulted in higher remission rates and prolonged disease-free survival, even in high risk patients. VP-16 levels have been measured in plasma at the time of transplantation. The question is, is there a biological activity that corresponds with the risk of delayed engraftment or graft failure? We investigated the inhibitory effects of plasma samples obtained from patients under high-dose VP-16 therapy on the growth of human bone marrow progenitor cells. Bone marrow cells from healthy donors were exposed to the plasma samples and seeded into methylcellulose-culture (CFU-C-assay). We found a dose dependent CFU-C inhibition related to VP-16 plasma levels at the time of transplantation (k = 0.769, P < 0.01). There were signs of a correlation between CFU-C growth inhibition at the time of BMT and haematological recovery (k = 0.656, P < 0.05) between CFU-C inhibition and the time until leucocytes reached 0.2 x 10(9)/l. Patients with CFU-C growth inhibition at the time of BMT may show delayed engraftment of leucocytes and that there might be a correlation with VP-16 levels, but further investigation is necessary to determine the significance of the latter thesis and if VP-16 plasma levels could lead to failure of engraftment. We recommend a minimum time interval between VP-16 infusion and graft transplantation of 72 h.
Asunto(s)
Trasplante de Médula Ósea , Etopósido/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Neoplasias/sangre , Adolescente , Adulto , Niño , Etopósido/sangre , Células Madre Hematopoyéticas/citología , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Neoplasias/patología , Neoplasias/terapia , Células Tumorales Cultivadas , Ensayo de Tumor de Célula MadreRESUMEN
Iodo-doxorubicin belongs to the group of doxorubicin analogs with modifications at the 4'-position of the daunosamine sugar moiety. Epirubicin is the archetype of the analogs created by configurational changes at the sugar. In case of EPI, the hydroxy group at the 4'-position is equatorial instead axial. In case of I-DOX, the hydroxy group has been replaced by an iodine-atom. This exchange has a great influence on the basicity of the amino group at the 3'-position. The physico-chemical properties of I-DOX are markedly different from those of DOX and EPI. I-DOX is unprotonated at physiological pH and much more lipophilic than DOX. The preclinical screening showed greater potency of I-DOX in different tumor cell systems. Cardiotoxicity and tissue toxicity after extravasation were significantly reduced in case of I-DOX. The substance was evaluated within three phase-I-studies in Europe during 1988 to 1990. The most prominent toxicity observed was myelotoxicity. This type of toxicity was dose-dependent and reversible. Alopecia, stomatitis/mucositis were not seen at all. There was only minor nausea without vomiting. The measured thyroid parameters were not affected by administration of an iodine-containing drug, but long-term effects cannot be ruled out. No acute cardiotoxicity was observed. The pharmacokinetics and metabolism of I-DOX differ from those of DOX and EPI. The terminal half-life of I-DOX is shorter, the plasma clearance higher than of DOX. One major difference is the formation of iodo-doxorubicinol, which is much larger in case of I-DOX compared to DOX and EPI. This cytostatic metabolite has a long terminal half-life.
Asunto(s)
Doxorrubicina/análogos & derivados , Neoplasias/tratamiento farmacológico , Células Tumorales Cultivadas/efectos de los fármacos , Animales , Línea Celular , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapéutico , Resistencia a Medicamentos , HumanosRESUMEN
Eighteen patients with advanced squamous cell carcinoma of the esophagus without prior chemotherapy were treated with carboplatin. Based on experimental data a split dose of carboplatin of 130 mg/m2 given on days 1, 3 and 5 was administered. In cases showing no WBC and platelet suppression, an escalated dose of 160 mg/m2 was proposed. Out of 18 evaluable patients no complete and partial responses were observed and there were only 5 patients with stable disease (27.8%) lasting 2-7 months. Therefore, carboplatin in the regimen used shows no meaningful antitumor activity in patients with advanced esophageal carcinoma. The escalated dose (mean 107-123% of the starting dose) was well tolerated and was followed by only minor gastrointestinal and hematological toxicity. Therefore, this regimen can be recommended for future trials.
Asunto(s)
Antineoplásicos , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Adulto , Anciano , Carboplatino , Evaluación de Medicamentos , Femenino , Estudios de Seguimiento , Alemania Occidental , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/efectos adversosRESUMEN
4'-Epidoxorubicin, doxorubicin (internal standard) and eight metabolites were extracted from heart tissue homogenate by a mixture of tetrahydrofuran-water (1:2, v/v) and purified by C18 Sep-Pak cartridges. The buffer used to prepare the homogenate contained glucaric acid-1,4-lactone and glucose, to prevent decomposition of the 4'-epidoxorubicin glucuronides. Anthracyclines were separated by high-performance liquid chromatography within 14 min and detected by fluorescence. Recoveries ranged from 49 to 75%. The detection limits of the individual anthracyclines ranged from 0.5.10(-11) to 2.5.10(-11) mol/g wet weight. The peak-height ratios of the fluorescence intensities of the anthracyclines versus doxorubicin were linear from 2.5.10(-11) to 250.10(-11) mol/g wet weight. Within- and between-day precisions of the assay varied between the anthracyclines and were in the ranges 3-12% (n = 6) and 2-11% (n = 6), respectively.
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Doxorrubicina/análisis , Miocardio/análisis , Animales , Cromatografía Líquida de Alta Presión , Epirrubicina , Masculino , Ratones , Ratones Endogámicos DBARESUMEN
4'-Epidoxorubicin, its seven metabolites and doxorubicin, as internal standard, were efficiently extracted from plasma using C18 Sep-Pak cartridges. The recoveries ranged from 58% for doxorubicin aglycone up to 98% for 4'-epidoxorubicin glucuronide. The anthracyclines were separated by reversed-phase high-performance liquid chromatography within 9 min and analysed by fluorescence. The assay was sensitive to 3 X 10(-10) M for the glucuronides up to 12 X 10(-10) M for 7-deoxydoxorubicin aglycone. The peak-height ratio of the fluorescence intensities of the anthracyclines versus doxorubicin showed a linear correlation with the concentration from the detection limit up to 2.5 X 10(-7) M (correlation coefficient r2 greater than 0.99). Within-day and between-day precision of the assay were in the ranges 2-14% (n = 6) and 2-11% (n = 6), respectively.
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Doxorrubicina/sangre , Biotransformación , Cromatografía Líquida de Alta Presión , Doxorrubicina/farmacocinética , Epirrubicina , HumanosRESUMEN
Metabolism of epidoxorubicin was studied in plasma of seven different animal species at 2 h after administration of 4 mg/kg. None of the animals showed significant glucuronidation of epidoxorubicin, although small amounts of the glucuronides could be detected in the rabbit. However, large differences in formation of epidoxorubicinol and 7-deoxy (7d) doxorubicinol aglycone were observed between the species. These phenomena may be relevant for interspecies differences with regard to anthracycline-induced histomorphological changes in for example, heart tissues and cardiotoxicity in relation to formation of 7d aglycones.
Asunto(s)
Doxorrubicina/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Doxorrubicina/sangre , Epirrubicina , Glucuronidasa/metabolismo , Cobayas , Humanos , Ratones , Conejos , Ratas , Especificidad de la EspecieRESUMEN
The clinical significance of the radioimmunological determination of tissue polypeptide antigen (TPA) was studied in 1980 and 1981 in patients with different cancer types (cancer of the gastrointestinal tract, cancer of the genitourinary tract, cancer of the lung and other malignancies) as well as in patients with acute inflammatory diseases, other benign diseases and healthy controls. TPA levels were elevated in about 70% of patients with acute inflammatory diseases and in 50-80% of patients with malignancies having evidence of disease (ED). In all other groups, as healthy controls, benign diseases except inflammatory diseases and cancer patients who had no evidence of disease (NED) or partial remission (PR), TPA was above the normal range in 4-17%. Comparisons between cancer patients with ED and cancer patients with NED/PR, healthy controls and patients with benign diseases (without acute inflammatory diseases) have shown a significant difference (p less than 0.01). Data from a follow-up program from the years 1982 to 1984, including TPA determinations, are shown. TPA can be regarded as an additional 'marker' for proliferative processes. The test seems to be useful for monitoring cancer growth in advanced cancer patients who received chemo- or radiotherapy. Limitations result from the lack of tumor specificity of the marker TPA.