Among methylating agents of clinical interest, temozolomide is a novel antitumor compound that has raised particular interest due to its acceptable safety profile and activity against tumors poorly responsive to conventional chemotherapy, such as malignant glioma and metastatic melanoma. Moreover, the drug has recently shown promising antitumor activity in a patient affected by primary brain lymphoma and is currently under phase II clinical trials for leptomeningeal metastases from leukemia and lymphoma or for brain metastases from lung and breast cancers. The antitumor activity of TMZ, that generates different types of methyl adducts (70% N7-methylguanine, 10% N3-methyladenine and 9% O6-methylguanine), has been mainly attributed to the formation of O6-methylguanine adducts. Indeed, tumor cell susceptibility to TMZ is strongly affected by the functional status of DNA repair systems, involved either in the removal of methyl adducts from O6G or in the apoptotic signaling triggered by O6-methylG:T mispairs. This review will focus on the different pharmacological strategies aimed at overcoming tumor resistance to TMZ such as new formulations of the drug or dosing schedules, and combined treatments with other chemotherapeutic agents, modulators of DNA repair systems, or gene therapy. The potential use of N3-methyladenine selective agents in the case of tumors tolerant to O6-methylguanine will be also discussed.

Tentori, L., Graziani, G. (2002). Pharmacological strategies to increase the antitumor activity of methylating agents. CURRENT MEDICINAL CHEMISTRY, 9(13), 1285-1301.

Pharmacological strategies to increase the antitumor activity of methylating agents

TENTORI, LUCIO;GRAZIANI, GRAZIA
2002-01-01

Abstract

Among methylating agents of clinical interest, temozolomide is a novel antitumor compound that has raised particular interest due to its acceptable safety profile and activity against tumors poorly responsive to conventional chemotherapy, such as malignant glioma and metastatic melanoma. Moreover, the drug has recently shown promising antitumor activity in a patient affected by primary brain lymphoma and is currently under phase II clinical trials for leptomeningeal metastases from leukemia and lymphoma or for brain metastases from lung and breast cancers. The antitumor activity of TMZ, that generates different types of methyl adducts (70% N7-methylguanine, 10% N3-methyladenine and 9% O6-methylguanine), has been mainly attributed to the formation of O6-methylguanine adducts. Indeed, tumor cell susceptibility to TMZ is strongly affected by the functional status of DNA repair systems, involved either in the removal of methyl adducts from O6G or in the apoptotic signaling triggered by O6-methylG:T mispairs. This review will focus on the different pharmacological strategies aimed at overcoming tumor resistance to TMZ such as new formulations of the drug or dosing schedules, and combined treatments with other chemotherapeutic agents, modulators of DNA repair systems, or gene therapy. The potential use of N3-methyladenine selective agents in the case of tumors tolerant to O6-methylguanine will be also discussed.
2002
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/14 - FARMACOLOGIA
English
Con Impact Factor ISI
6 o benzylguanine; 8 hydroxy 2 methyl 4(3h) quinazolinone; adenine; alkylating agent; angiogenesis inhibitor; antineoplastic agent; carboplatin; carmustine; cisplatin; dacarbazine; DNA topoisomerase inhibitor; docetaxel; fotemustine; fumagillol chloroacetylcarbamate; ganciclovir; gefitinib; guanine; irinotecan; marimastat; matrix metalloproteinase inhibitor; methoxyamine; methyl group; protein p53; streptozocin; sulfonic acid derivative; temozolomide; thalidomide; thymidine kinase; transferase inhibitor; unclassified drug; unindexed drug; animal experiment; animal model; antineoplastic activity; apoptosis; blood toxicity; bone marrow suppression; brain lymphoma; brain metastasis; breast cancer; central nervous system metastasis; clinical trial; controlled clinical trial; controlled study; DNA repair; dose response; drug formulation; drug potentiation; drug response; drug safety; drug sensitivity; drug structure; glioblastoma; human; leptomeninx; leukemia; liver toxicity; lung cancer; lung toxicity; lymphoma; melanoma; metastasis; mouse; musculoskeletal disease; nonhuman; randomized controlled trial; review; signal transduction; tumor cell; viral gene therapy; Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Combined Modality Therapy; Dacarbazine; DNA Methylation; DNA Repair; Humans; Mice; O(6)-Methylguanine-DNA Methyltransferase
Tentori, L., Graziani, G. (2002). Pharmacological strategies to increase the antitumor activity of methylating agents. CURRENT MEDICINAL CHEMISTRY, 9(13), 1285-1301.
Tentori, L; Graziani, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/52889
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