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 ...
Gastropods from five elk foraging areas in north central Pennsylvania were collected from June to September 1981 and 1982 and examined for Parelaphostrongylus tenuis larvae. A total of 445 snails were found with a prevalence of infection of 16.2%. Seven species of snails were collected; larvae were found in six, and three represent new reports of naturally infected intermediate hosts of P. tenuis. These were Triodopsis albolabris, T. tridentata, and Ventridens intertextus. The prevalence of infection in each of these species was 20, 11.8, and 20.3%, respectively. Of 363 slugs, belonging to three species, only 1 (Deroceras laeve) was infected. One site, an old reclaimed strip mine, yielded 81% of the collected snails and 91.7% of the infected snails. This site was distinctive in its dense interwoven ground cover and soil of high calcium content and neutral pH.
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