Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating species.

Cloretazine [1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine; VNP40101M; 101M] is a relatively new prodrug with activity in elderly acute myelogenous leukemia (AML) patients. Its therapeutic action is due largely to the production of 1-(3-cytosinyl),2-(1-guanyl)ethane cross-links (G-C ethane cross-links) in DNA. The numbers of cross-links produced in three experimental leukemia lines (L1210, U937 and HL-60) were fewer than 10 per genome at their respective LC50 concentrations. Only 1 in approximately 20,000 90CE molecules produces a cross-link in the AGT (O6-alkylguanine-DNA alkyltransferase) negative L1210 and U937 cell lines and 1 in 400,000 in the AGT positive HL-60 cell line.
AuthorsPhilip G Penketh, Raymond P Baumann, Kimiko Ishiguro, Krishnamurthy Shyam, Helen A Seow, Alan C Sartorelli
JournalLeukemia research (Leuk Res) Vol. 32 Issue 10 Pg. 1546-53 (Oct 2008) ISSN: 0145-2126 [Print] England
PMID18479747 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine
  • Antineoplastic Agents
  • Cross-Linking Reagents
  • Hydrazines
  • Sulfonamides
  • laromustine
  • Guanine
  • Cytosine
  • DNA
  • Ethane
  • Animals
  • Antineoplastic Agents (chemistry, therapeutic use, toxicity)
  • Cell Line, Tumor
  • Cross-Linking Reagents (chemistry, toxicity)
  • Cytosine (chemistry)
  • DNA (chemistry)
  • Ethane (chemistry)
  • Guanine (chemistry)
  • HL-60 Cells
  • Humans
  • Hydrazines (chemistry, therapeutic use, toxicity)
  • Leukemia (drug therapy)
  • Mice
  • Sulfonamides (chemistry, therapeutic use, toxicity)
  • U937 Cells

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