O6-methylguanine-DNA methyltransferase activity and sensitivity to cyclophosphamide and cisplatin in human lung tumor xenografts

Abstract

The DNA repair protein O6‐methylguanine‐DNA methyltransferase (MGMT) is a main determinant of resistance of cells to the cytostatic effects of O6‐alkylguanine‐generating alkylating agents. The purpose of our study was to assay MGMT activity in cells of lung cancers and to correlate MGMT levels with chemotherapy response to cyclophosphamide (CTX) and cisplatin (DDP). MGMT levels were determined in 14 human lung tumor xenografts. There was a wide variation of MGMT expression in these tumors, ranging from 10 to 984 fmol/mg protein. There was also a wide range in the sensitivity of the xenografts to CTX and DDP, as measured by specific growth delay. When the MGMT levels of the different xenograft lines were compared with the corresponding responses to CTX and DDP, a close correlation was found between MGMT activity and CTX (lin reg., r = –0.83, p < 0.05). The higher the MGMT activity, the less pronounced was the growth‐inhibiting effect of CTX. With DDP, no such correlation was found. Our results indicate that the in vivo response of tumors to CTX is related to the level of MGMT expression. Int. J. Cancer 77:919–922, 1998. © 1998 Wiley‐Liss, Inc.

CpG Island Hypermethylation of the DNA Repair Enzyme Methyltransferase Predicts Response to Temozolomide in Primary Gliomas

“…The potential of MGMT methylation to pinpoint tumors that are more sensitive to alkylating agents may extend to other non-BCNU-like alkylating drugs such as cyclophosphamide (41,42). This has been demonstrated in vivo in diffuse large cell lymphomas treated with chemotherapeutic regimens, including the alkylating agent cyclophosphamide (26), where MGMT hypermethylation was the strongest predictor of overall survival and time-to-progression and was far superior to classical clinical factors such as the International Prognostic Index (26).…”

Secreted Frizzled Related Protein 1 Modulates Taxane Resistance of Human Lung Adenocarcinoma

“…We have identified the miRNA expression profile involved in the development of docetaxel resistance in LAD by miRNA microarray (14,21,22). DNA methylation also plays critical roles in the development of chemoresistance by downregulating tumor suppressors, apoptosis mediators and DNA repair enzymes (23,24). Recently, the association of DNA methylation with the sensitivity of tumor cells to taxanes also was reported.…”

Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer

“…The potential of MGMT to predict the chemoresponse of human tumors to alkylating agents is not limited to BCNU-like alkylating agents, but it may extend to other drugs such as cyclophosphamide (Mattern et al, 1998;Cai et al, 1999;Friedman et al, 1999;Gamcsik et al, 1999), but not cisplatin (Mattern et al, 1998). This has been demonstrated in vivo in diffuse large-cell lymphomas treated with chemotherapeutic regimens including the alkylating agent cyclophosphamide (Esteller et al, 2002c), where MGMT hypermethylation was the strongest predictor of overall survival and time to progression, and was far superior to classical clinical factors such as the International Prognostic Index (IPI) (Esteller et al, 2002c).…”