1,3-Bis(2-Chloroethyl)-1-Nitrosourea (Bcnu) And Other Nitrosoureas In Cancer Treatment: A Review

Carter, Stephen K.; Schabel, Frank M.; Broder, Lawrence E.; Johnston, Thomas P.

doi:10.1016/s0065-230x(08)60343-7

Cited by 150 publications

(39 citation statements)

References 24 publications

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“…Studies on nitrosourea derivatives started from the investigations on anti-tumor effects against mouse leukemia L 1210 of MNNG, which possessed carcinogenicity rather than anti-tumor activity (Greene and Greenberg 1960;Carter et al . 1972;Scheparz 1976).…”

Section: Discussionmentioning

confidence: 99%

Studies on the mechanism of action of ACNU, 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride: Effects on cultured HeLa S3 cells.

Kanamaru

Asamura

Sato

et al. 1980

Tohoku J. Exp. Med.

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Section: Discussionmentioning

confidence: 99%

Studies on the mechanism of action of ACNU, 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride: Effects on cultured HeLa S3 cells.

Kanamaru

Asamura

Sato

et al. 1980

Tohoku J. Exp. Med.

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“…Representatives of the firstgeneration in this class, such as N,N'-bis-(2-chloroethyl)-N-nitrosourea (BCNU), N-(2-chloroethyl)-N'-cyclohexyl- (MeCCNU) (Fig. 1) were introduced into the clinic in the early 60s in rapid succession because of their activity against Hodgkin and non-Hodgkin lymphomas, brain tumours, gastrointestinal tumours and some other neoplasms (2). Their clinical application, however, is limited because they show delayed and cumulative toxic side effects, bone-marrow suppression being prevalent and dose-limiting.…”

Section: N-(2-chloroethyl)-n-nitrosoureasmentioning

confidence: 99%

Nitrosoureas Modes of Action and Perspectives in the Use of Hormone Receptor Affine Carrier Molecules

et al. 1989

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“…BCNU is particularly effective in treating childhood and adult glial tumors (2, 3) and has been used in high-dose chemotherapy for lymphomas, breast, lung, and gastrointestinal cancers (1,4). Unfortunately, the clinical success of the CNUs has been limited by their severe bone marrow and lung toxicities.…”

Section: Introductionmentioning

confidence: 99%

“…The chloroethylnitrosourea (CNU) chemotherapeutic alkylating agents have been used to treat certain kinds of cancer for over two decades (1), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmoustine) is typical of this class of chemotherapeutic drug. BCNU is particularly effective in treating childhood and adult glial tumors (2,3) and has been used in high-dose chemotherapy for lymphomas, breast, lung, and gastrointestinal cancers (1,4).…”

mentioning

confidence: 99%

Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic alkylating agent.

Maze

Carney

Kelley

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

104

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The chloroethylnitrosourea (CNU) alkylating agents are commonly used for cancer chemotherapy, but their usefulness is limited by severe bone marrow toxicity that causes the cumulative depletion of all hematopoietic lineages (pancytopenia). Bone marrow CNU sensitivity is probably due to the inefficient repair of CNU-induced DNA damage; relative to other tissues, bone marrow cells express extremely low levels of the 06-methylguanine DNA methyltransferase (MGMT) protein that repairs cytotoxic 06-chloroethylguanine DNA lesions. Using a simplified recombinant retroviral vector expressing the human MGMT gene under control of the phosphoglycerate kinase promoter (PGK-MGMT) we increased the capacity of murine bone marrow-derived cells to repair CNU-induced DNA damage. Stable reconstitution of mouse bone marrow with genetically modified, MGMTexpressing hematopoietic stem cells conferred considerable resistance to the cytotoxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a CNU commonly used for chemotherapy. Bone marrow harvested from mice transplanted with PGK-MGMT-transduced cells showed extensive in vitro BCNU resistance. Moreover, MGMT expression in mouse bone marrow conferred in vivo resistance to BCNU-induced pancytopenia and significantly reduced BCNU-induced mortality due to bone marrow hypoplasia. These data demonstrate that increased DNA alkylation repair in primitive hematopoietic stem cells confers multilineage protection from the myelosuppressive effects of BCNU and suggest a possible approach to protecting cancer patients from CNU chemotherapy-related toxicity.The chloroethylnitrosourea (CNU) chemotherapeutic alkylating agents have been used to treat certain kinds of cancer for over two decades (1), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmoustine) is typical of this class of chemotherapeutic drug. BCNU is particularly effective in treating childhood and adult glial tumors (2, 3) and has been used in high-dose chemotherapy for lymphomas, breast, lung, and gastrointestinal cancers (1,4). Unfortunately, the clinical success of the CNUs has been limited by their severe bone marrow and lung toxicities. Myelosuppression is characteristically delayed following CNU treatment and can lead to severe, prolonged, and cumulative pancytopenia (3). The extreme sensitivity of bone marrow to CNUs may be explained by the inability of this tissue to repair CNU-induced cytotoxic DNA damage efficiently (5).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.CNU alkylation produces numerous DNA base modifications plus DNA inter-and intrastrand crosslinks. Interstrand crosslinks are particularly cytotoxic because they grossly interfere with DNA replication; their formation can be initiated by a chloroethyl group at the 06 position of guanine which slowly rearranges to form an ethyl bridge between NI of guanine and N3 of cytosine in the opposite ...

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1,3-Bis(2-Chloroethyl)-1-Nitrosourea (Bcnu) And Other Nitrosoureas In Cancer Treatment: A Review

Cited by 150 publications

References 24 publications

Studies on the mechanism of action of ACNU, 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride: Effects on cultured HeLa S3 cells.

Studies on the mechanism of action of ACNU, 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride: Effects on cultured HeLa S3 cells.

Nitrosoureas Modes of Action and Perspectives in the Use of Hormone Receptor Affine Carrier Molecules

Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic alkylating agent.

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