DNA interstrand cross-linking and cytotoxicity induced by chloroethylnitrosoureas and cisplatin in human glioma cell lines which vary in cellular concentration of O6-alkylguanine-DNA alkyltransferase

Abstract

Summary Fifteen human glioma cell lines were examined for their sensitivity to 1 ,3-bis(chloroethyl)-nitrosourea (BCNU, carmustine) and cisdichlorodiamminoplatinum (cisplatin), the induction of DNA interstrand cross-linking (DNA-ISC) induced by the two agents and cellular 06_ alkylguanine alkyltransferase (ATase) activity. Cell lines differed in their sensitivities to BCNU by up to 12-fold and to cisplatin by up to 21 -fold. For both drugs, the extent of DNA-ISC was related to the drug sensitivity. There was a wide range of cellular ATase levels. Increasing ATase levels correlated with increased resistance to BCNU and with decreased formation of DNA-ISC following treatment with BCNU. In contrast, following treatment with cisplatin, there was no correlation between cellular ATase content and cytotoxicity or between ATase and DNA-ISC. Four sublines of varying ATase activity were prepared from one of the cell lines. These sublines showed a sensitivity to BCNU in inverse proportion to ATase activity, while sensitivity to cisplatin was more uniform. The experiments confirm the direct relationship between ATase concentration and sensitivity to BCNU in glioma cells. Although there was some correlation between cisplatin cytotoxicity and BCNU cytotoxicity, this was not mediated through ATase.

Preliminary Individualized Chemotherapy for Malignant Astrocytomas Based on O6-Methylguanine-Deoxyribonucleic Acid Methyltransferase Methylation Analysis

“…Moreover, of the MGMT-methylated tumors, there are only two glioblastomas, and one of these had only a biopsy (Case 6) whereas the other had a resection but was listed as NE, or not able to be evaluated (Case 9). Indeed, of the seven MGMTmethylated tumors, more (4) are listed as``not able to be evaluated'' than those that were evaluable (3). Thus it is difficult with such small numbers to come to a definitive conclusion.…”

“…8,11,16) However, combination chemotherapy with CDDP or CBDCA and VP-16 as the second line chemotherapy following nitrosourea failure has shown encouraging results. 1,10,23) Furthermore, the antitumor activity of platinum compounds is not related to MGMT activity, 3,17) so platinum compounds are good candidates for the treatment of MGMT-unmethylated tumors.…”

O6-methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma

“…Unlike O 6 ‐alkylguanine alkylating agents, there is a controversy existing between the MGMT activity and the cytotoxicity of CDDP. Although several studies have shown that the cytotoxicity of CDDP is correlated with expression levels of MGMT, certain studies have contradicted this finding . In addition, whether MGMT expression could impact the CDDP efficacy and the clinical prognosis in NPC patients has not been examined.…”

“…Although several studies have shown that the cytotoxicity of CDDP is correlated with expression levels of MGMT, certain studies have contradicted this finding. [14][15][16][17][18] In addition, whether MGMT expression could impact the CDDP efficacy and the clinical prognosis in NPC patients has not been examined. In this study, we investigated cellular responses and explored mechanistic analyses between MGMT expression and CDDP in NPC cells; we also analyzed the clinical significance of MGMT expression in NPC patients treated with CDDP-based CCRT.…”

Selection of chemotherapy for glioblastoma expressing O6-methylguanine-DNA methyltransferase

“…The platinum agents as well as temozolomide and O 6 -benzylguanine can abrogate MGMT activity (22). Several studies have also shown that the antitumor activity of platinum agents is not affected by MGMT activity (23)(24)(25). This knowledge has led to Phase II clinical trials with promising results (26)(27)(28).…”