Chemotherapy of experimental meningeal gliomatosis

Abstract

Experimental models of meningeal gliomatosis (MG) were established by intracisternal inoculation of rat C6 and 9L gliomas. The response of these experimental models to chemotherapy and in vitro chemosensitivity were studied in both cell lines. Cell suspensions of 1 × 107 C6 and 9L glioma cells were injected subcutaneously into the cisterna magna of Wistar and Fisher 344 rats, respectively. The tumor cells inoculated into the cisternae of the rats developed rapidly and the rats died in approximately 20 days. The pathophysiology of these MG models was similar to that of human MG. MG rats were treated by intravenous administration of bleomycin (BLM, 5 mgkg), 1-(4amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU, 15 mgkg), 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU, 15 mgkg), or by a combination of BLM and ACNU or BCNU on Day 5 after inoculation. In the rats inoculated with C6 glioma cells, the control group had a mean survival time of 14.3±2.9 (SD) days, and single-agent chemotherapy failed to prolong the mean survival time. In the rats inoculated with 9L glioma cells, the control animals had a similar mean survival time of 14.3±3.1 days, but single-agent chemotherapy with ACNU or BCNU prolonged the mean survival time to 25.7±5.2 days and 26.8±4.3 days, respectively. Combined therapy using BLM and ACNU or BCNU increased the mean survival time to 37.5±8.8 days and 39.1±8.1 days, respectively. These survival times were significantly longer than those obtained with single-agent therapy. In vitro chemosensitivity assay was carried out by the monolayer culture technique. Cytotoxic activity of ACNU was measured by determining the drug concentration for 50% growth inhibition (IC50), which was obtained by plotting the logarithm of the drug concentration against the growth rate (percentage of control) of the treated cells. The IC50 values of ACNU for C6 and 9L glioma cells were 8.3 μgml and 0.88 μgml, respectively. C6 glioma cells were more resistant to ACNU than 9L glioma cells. It was concluded that in vitro chemosensitivity assay correlated with in vivo chemosensitivity assay in MG models and that these MG models were useful as a chemosensitivity assay system in vivo.