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1.
Gynecol Oncol ; 76(3): 362-8, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10684711

RESUMEN

OBJECTIVES: We have established a panel of 15 human ovarian cancer xenografts grown subcutaneously in the flank of the nude mouse. Similar to the clinic, the xenografts show differences in histological subtype and volume doubling time. We determined whether the panel is useful for drug screening by testing the sensitivity to six conventional anticancer agents. In addition, we investigated whether the glutathione detoxification system affects sensitivity to cisplatin and cyclophosphamide, major drugs in the treatment of ovarian cancer. METHODS: Mice bearing well-established tumors were treated at maximum tolerated doses as defined by a reversible weight loss up to 15% of their initial weight: cisplatin 5 mg/kg iv weekly x2, cyclophosphamide 150 mg/kg ip 2-weekly x2, doxorubicin 8 mg/kg iv weekly x2, hexamethylmelamine ip 150 mg/kg every other day x4, methotrexate ip 150 mg/kg weekly x2, and 5-fluorouracil 60 mg/kg ip weekly x4. Glutathione levels and the activities of three different glutathione-dependent enzymes were measured in untreated xenograft tissues. RESULTS: Growth inhibition >75% was reached for cisplatin in 40%, for cyclophosphamide in 27%, and for doxorubicin in 20% of the xenografts. Methotrexate and 5-fluorouracil did not induce growth inhibition of importance. Hexamethylmelamine showed >75% growth inhibition in 53% of the xenografts, which may have been caused by the favorable metabolism of the drug in mice when compared with that in patients. Glutathione levels varied 3.6-fold in the xenografts and did not show a relation with sensitivity to cisplatin, cyclophosphamide, or doxorubicin. No relation was found between the activities of glutathione S-transferase and glutathione peroxidase and the sensitivities to the three anticancer agents. Glutathione reductase activity, however, showed a weak, inverse relation with the efficacy of cisplatin and cyclophosphamide (r values of -0.55 and -0.58, respectively). CONCLUSIONS: The sensitivity to the six anticancer agents of our panel of 15 human ovarian cancer xenografts reflects the response rates known for similar drugs in ovarian cancer patients. In that respect, the panel may be useful for drug screening as well as studies on the relevance of drug resistance features in vivo. The various components of the glutathione detoxification system did not predict for primary drug resistance which confirms clinical data in ovarian cancer.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Glutatión/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Animales , Cisplatino/farmacología , Ciclofosfamida/farmacología , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Inactivación Metabólica , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Células Tumorales Cultivadas
2.
Clin Cancer Res ; 3(10): 1747-54, 1997 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9815559

RESUMEN

The cumulative dose-related cardiotoxicity of doxorubicin is believed to be caused by the production of oxygen- free radicals. 7-Monohydroxyethylrutoside (monoHER), a semisynthetic flavonoid and powerful antioxidant, was investigated with respect to the prevention of doxorubicin-induced cardiotoxicity in mice and to its influence on the antitumor activity of doxorubicin in vitro and in vivo. Non-tumor-bearing mice were equipped with a telemeter in the peritoneal cavity. They were given six weekly doses of 4 mg/kg doxorubicin i.v., alone or in combination with either 100 or 250 mg/kg monoHER i.p., 1 h prior to doxorubicin administration and for the following 4 days. Cardiotoxic effects were measured from electrocardiogram changes up to 2 weeks after treatment. Protection against cardiotoxicity was found to be dose dependent, with 53 and 75% protection, respectively, as calculated from the reduction in the increase in the ST interval. MonoHER and several other flavonoids with good antioxidant properties were tested for their antiproliferative effects in the absence or the presence of doxorubicin in A2780 and OVCAR-3 human ovarian cancer cells and MCF-7 human breast cancer cells in vitro. Some flavonoids were directly toxic at 50 and 100 microM, whereas others, including monoHER, did not influence the antiproliferative effects of doxorubicin at these concentrations. The influence of monoHER was further tested on the growth-inhibitory effect of 8 mg/kg doxorubicin i.v., given twice with an interval of 1 week in A2780 and OVCAR-3 cells that were grown as s.c. xenografts in nude mice. MonoHER, administered 1 h before doxorubicin in a dose schedule of 500 mg/kg i.p. 2 or 5 days per week, was not toxic and did not decrease the antitumor activity of doxorubicin. It can be concluded that monoHER showed a dose-dependent protection against chronic cardiotoxicity and did not influence the antitumor activity of doxorubicin in vitro or in vivo.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Antioxidantes/farmacología , Cardiomiopatías/prevención & control , Doxorrubicina/farmacología , Flavonoides/farmacología , Hidroxietilrutósido/farmacología , Quempferoles , Animales , Antibióticos Antineoplásicos/uso terapéutico , Antibióticos Antineoplásicos/toxicidad , Antioxidantes/administración & dosificación , Antioxidantes/uso terapéutico , Antioxidantes/toxicidad , Neoplasias de la Mama/patología , Cardiomiopatías/inducido químicamente , Catequina/administración & dosificación , Catequina/farmacología , Catequina/uso terapéutico , Terapia por Quelación , Cistadenocarcinoma Seroso/patología , Relación Dosis-Respuesta a Droga , Doxorrubicina/uso terapéutico , Doxorrubicina/toxicidad , Interacciones Farmacológicas , Electrocardiografía , Femenino , Flavonoides/administración & dosificación , Flavonoides/uso terapéutico , Flavonoides/toxicidad , Flavonoles , Depuradores de Radicales Libres , Radicales Libres , Humanos , Hidroxietilrutósido/uso terapéutico , Hierro , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Quelantes del Hierro/toxicidad , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Neoplasias Ováricas/patología , Quercetina/administración & dosificación , Quercetina/análogos & derivados , Quercetina/farmacología , Quercetina/uso terapéutico , Quercetina/toxicidad , Razoxano/administración & dosificación , Razoxano/farmacología , Razoxano/uso terapéutico , Razoxano/toxicidad , Rutina/administración & dosificación , Rutina/farmacología , Rutina/uso terapéutico , Rutina/toxicidad
3.
Eur J Cancer ; 29A(6): 897-906, 1993.
Artículo en Inglés | MEDLINE | ID: mdl-8484984

RESUMEN

EO9 is a novel and fully synthetic bioreductive alkylating indoloquinone. Although structurally-related to mitomycin C, EO9 exhibits a distinct preclinical antitumour profile and there are also differences in its biochemical activation. In this study, EO9 was found to demonstrate preferential cytotoxicity against solid tumours in vitro as compared to leukaemia cell lines both in the Corbett two-tumour assay and in the disease-oriented human tumour cell line panel of the U.S. National Cancer Institute. In the latter system activity was particularly apparent in colon, melanoma and central nervous system lines, together with some renal and non-small cell lung lines. Preferential cytotoxicity towards hypoxic versus aerobic EMT6 mouse mammary tumour cells was observed. In vivo, EO9 was inactive against the P388 murine leukaemia, while exerting significant antiproliferative effects against several murine and human solid tumours, including the generally resistant MAC mouse colon tumours and gastric, ovarian and breast xenografts. These results confirmed in vitro observations of preferential solid tumour activity. In animal toxicology studies, EO9 induced vascular congestion in the gastrointestinal tract, but no significant bone marrow toxicity. The LD10 value of EO9 after a single intravenous injection into mice was 9 mg/kg (27 mg/m2). A dose of one-tenth of the mouse equivalent LD10 (2.7 mg/m2), the recommended starting dose for clinical phase I studies, was found to be safe in rats. Considering its distinct mechanism of bioactivation as compared to mitomycin C, its preferential solid tumour activity, its excellent activity against hypoxic cells, and lack of significant bone marrow toxicity in animals studies, EO9 has been selected for clinical evaluation within the framework of the EORTC.


Asunto(s)
Antineoplásicos/uso terapéutico , Aziridinas/uso terapéutico , Indolquinonas , Indoles/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Animales , Aziridinas/toxicidad , Médula Ósea/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Indoles/toxicidad , Leucemia P388/tratamiento farmacológico , Masculino , Ratones , Trasplante de Neoplasias , Ratas , Células Tumorales Cultivadas/efectos de los fármacos
4.
In Vivo ; 1(1): 1-13, 1987.
Artículo en Inglés | MEDLINE | ID: mdl-2979758

RESUMEN

In an attempt to increase the predictability of preclinical antitumor testing, the value of human tumor lines in immune-deficient nude mice is assessed by reviewing the relevant literature. This test model is rather elaborate due to the nature of the animal as well as test and evaluation procedure. However, it represents a realistic simulation of clinical drug treatment. This is demonstrated by (a) a good correlation of drug effects in the nude mouse with clinical results in the donating patient's tumor and (b) by a good predictability of a panel of human tumor lines for clinically effective drugs. In order to avoid clinical trials with inactive drugs and no therapeutic benefit for a large number of patients, the application of human tumor xenografts in anticancer drug development is warranted.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Trasplante Heterólogo , Animales , Evaluación Preclínica de Medicamentos/métodos , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias/patología
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