Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Busulphan [1,4-bis(methanesulfonoxy)butane], an alkylating agent used in the treatment of chronic myelocytic leukemia, was labeled with the positron-emitting radionuclide carbon-11 in a four-step synthetic procedure [1-11C]4-Hydroxybutyronitrile was obtained in 60-70% yield by the reaction of [11C]cyanide with 3-bromopropanol. The nitrile was hydrolysed to [1-11C]gamma-butyrolactone (80-90% yield) with sulfuric acid. Solid phase extraction was used to isolate the lactone and change the solvent before reduction to [1-11C]1,4-butanediol. Dimesylation of the diol with methanesulfonyl chloride in dichloromethane/pyridine yielded [1-11C]busulphan with conversions in the order of 30-35%. The total time of synthesis, including HPLC purification, was 65-75 min from the end-of-trapping of [11C]ammonium cyanide. The decay-corrected isolated yield of no-carrier-added [11C]busulphan was 4-7% and the radiochemical purity was better than 99%.
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PMID:11C-labeling of busulphan. 166 12

Busulfan (1,4-butanediol dimethanesulfonate) has been used widely for the treatment of patients with chronic myelogenous leukemia. Busulfan is bifunctional and thus may effectively induce DNA damage, which may play an important role in the cytotoxicity. In this study, we compared the cytotoxicity of bifunctional busulfan with that of monofunctional ethyl methanesulfonate (EMS) in human promyelocytic leukemia HL-60 cells. Busulfan showed a significant inhibitory effect on cell growth, whereas the cells grew in the presence of EMS. To clarify the mechanism of cytotoxicity of busulfan, we investigated DNA damage induced by busulfan using 32P-5'-end-labeled DNA fragments obtained from the human p16 tumor suppressor gene. Busulfan induced DNA damage dose-dependently, whereas EMS caused little DNA damage. DNA-sequencing experiments using piperidine and 3-methyladenine DNA glycosylase indicated that busulfan caused double-base lesions mainly at 5'-GA-3' and, to a lesser extent, at 5'-GG-3' sequences. Time of flight mass spectrometry confirmed that busulfan forms an intrastrand cross-link at the 5'-GA-3' sequence, in addition to mono-alkylation. The mechanism and the role of cross-linking at the 5'-GA-3' sequence are discussed in relation to the cytotoxicity induced by busulfan.
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PMID:DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. 1513 75