Clinical and experimental adjuvant chemotherapy in case of drug resistant mechanism for human malignant glioma cells

Introduction: Adjuvant chemotherapy with cisplatin, Vincristine & ACNU (one of Nitrosourea anticancer drug) for malignant glioma during radiotherapy (mean dose: 55Gy) and for maintenance therapy is performed in our hospital. Such a chemotherapy elongates free time of tumor regrowth in anaplastic astrocytoma but shows minimal effects in gliobastoma. Some glioblastoma cases showed nearly complete responses with one or two courses of chemotherapy and radiation, but after some time suddenly tumor regrowth was found in spite of maintenance chemotherapy. Methods: Experimental human glioma cell lines were treated with cisplatin & ACNU in in vitro, in order to know why tumor size of many glioblastoma cases decreased with initial adjuvant chemotherapy but gradually increased afterwards. These chemotherapies demonstrated minimal effects on mean survival time. We made resistant cell lines for cisplatin and ACNU in A172 and T98G human glioma cell lines with repeated doses of cisplatin and ACNU (2-16 μM), respectively. Results: ACNU resistant cell lines were made by several exposures of ACNU in A172 cell lines. T98G cells are already ACNU resistant and this can be verified by measuring O6-methylguanine-DNA-methyltransferease with Northern blotting method. We could make resistant cells by cisplatin (over twenty times) in both lines. Step-up exposure of ACNU (0-240 μM) did not affect growth rate both in cisplatin resistant and in non-resistant A172 cell lines. Any concentration of cisplatin (0-200 μM) for ACNU resistant and original A172 and T98G cell lines showed the same growth rate. Conclusion: These results suggest that ACNU and cisplatin resistant mechanism for glioma cells is different, and the two established cell lines can be used to study drug resistant mechanism. ACNU and especially cisplatin seems to be a good combination for adjuvant chemotherapy in case of drug resistance.