In vitro drug sensitivity testing in human gliomas

Abstract

In vitro drug sensitivity assays have been developed with the goal of predicting the clinical response to chemotherapy. The colony-forming assay, radiolabeled precursor inhibition assay, and microcytotoxicity assay are most commonly used. In retrospective studies, the assays correctly predict clinical response to a chemotherapeutic agent in 50% to 70% of patients and predict clinical resistance in nearly 100% of patients. All of the assays suffer from technical and theoretical problems. In vitro assays depend on cell culture and therefore do not entirely simulate in vivo conditions. Heterogeneity in chemosensitivity is commonly found and can complicate the interpretation of results. Further investigation is needed to determine if these assays will be able to select prospective chemotherapy for patients. The malignant origin of the cells in culture must be verified if meaningful conclusions are to be made.

Ensayos de quimiosensibilidad en cultivos primarios de tumores cerebrales

“…Los criterios para medir la sensibilidad pueden expresarse de diversas formas, pero lo más corriente es expresar la concentración de la droga que resulta en un 0% de reducción de la colonia (IC 0). La curva dosis-respuesta obtenida puede ser del tipo 1: tumor completamente resistente a la droga ensayada; tipo 2: respuesta inicial, pero se alcanza un nivel estable que expresa la subpoblación de células resistentes; tipo 3: sensibilidad a partir de un umbral inicial a bajas concentraciones y tipo 4: respuesta similar al tipo 3 pero sin el "hombro" inicial (Figura 3) 12 . En nuestras experiencias, la mayor parte de las curvas corresponden al tipo 4, de morfología sigmoidea.…”

“…barrera hematoencefálica; el índice terapéutico o relación entre la eficacia/toxicidad a las concentraciones empleadas y la farmacocinética del agente citotóxico 12 .…”

Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas

“…However, the often described high chemosensitivity of these glioma cell cultures does not correspond to the poor response to chemotherapy seen in glioma patients. Lack of cellular heterogeneity is probably an important factor that contributes to this discrepancy: a cell line represents only a small subpopulation of the original tumour owing to selection during culture (Yung et al, 1982;Kimmel et al, 1987;Wetphal et al, 1988;Yung, 1989). The effects of cytostatic drugs on an alternative culture model for gliomas, OMS, are described.…”

“…In conventional in vitro drug testing assays with cell lines, cell killing (as in radiolabelled precursor inhibition assays or microcytotoxicty assays) or cell proliferation inhibition (as in colony-forming assays) is measured (Kimmel et al, 1987). In contrast, in OMS the histological cytotoxic effects of cytostatic drugs, as well as the inhibition of cell proliferation, can be studied in one sample.…”

“…Using these culture models it appeared that several drugs that are able to cross the BBB show a high cytolytic activity in vitro, whereas glioma patients respond poorly to these drugs (Yung et al, 1982;Kimmel et al, 1987;Yung 1989). Lack of cellular heterogeneity in the cell lines used and selection of themosensitive subpopulations during culture are the most likely explanation for this discrepancy (Yung et al, 1982;Kimmel et al, 1987;Westphal et al, 1988;Yung, 1989).…”