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.
Penketh
Philip G
PG
Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Baumann
Raymond P
RP
Ishiguro
Kimiko
K
Shyam
Krishnamurthy
K
Seow
Helen A
HA
Sartorelli
Alan C
AC
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000633:toxicity*; D003596:Cytosine / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D004980:Ethane / Q000737:chemistry; D006147:Guanine / Q000737:chemistry; D018922:HL-60 Cells; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D013449:Sulfonamides / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D020298:U937 Cells
C530954:1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D006834:Hydrazines; D013449:Sulfonamides; C483604:laromustine; D006147:Guanine; D003596:Cytosine; D004247:DNA; D004980:Ethane