Biomaterial Database

The cytotoxicity of thioguanine vs mercaptopurine in acute lymphoblastic leukemia. 1994

P C Adamson, and D G Poplack, and F M Balis

Pharmacology and Experimental Therapeutics Section, National Cancer Institute, Bethesda, Maryland 20892.

The use of mercaptopurine (MP) rather than thioguanine (TG) in the treatment of childhood acute lymphoblastic leukemia (ALL) has occurred for historical reasons, but does not have a pharmacologic basis. The purpose of this study was to begin to address whether TG would be more efficacious than MP in the treatment of childhood ALL. Preclinical cytotoxicity studies were performed using human leukemic cell lines and leukemic cells from patients with ALL. First, the concentration-survival curves for MP and TG in three human leukemic cell lines (MOLT-4, CCRF-CEM and Wilson) were determined. The second group of experiments determined the concentration-time dependence for cytotoxicity of MP and TG. The final group of experiments compared the in vitro cytotoxicity of MP to TG in leukemic cells from patients with ALL. The thiopurines displayed classical anti-metabolite cytotoxicity profiles, exhibiting a cytotoxicity threshold concentration and demonstrating an increase in cell kill with prolongation of exposure to the drug. For MP, the cytotoxicity threshold was approximately 1 microM, with maximum cytotoxicity occurring with 10 microM concentrations. For TG, the threshold was only 0.05 microM with maximum cytotoxicity occurring at 0.5 microM. Exposure to MP for more than 8 h was necessary to produce cytotoxicity, whereas exposures as short as 4 h were required for TG. Leukemic cells from children with ALL were also more sensitive to TG than to MP. The median IC50 for TG (20 microM) was significantly lower than that for MP (> or = 206 microM). The data presented here provide a strong rationale for evaluating TG in place of MP in the treatment of childhood ALL. The more direct intracellular activation pathway, higher potency, and shorter duration of drug exposure necessary for cytotoxicity all suggest that TG may have an advantage over MP.

UI	MeSH Term	Description	Entries
D002470	Cell Survival	The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.	Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D002648	Child	A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL.	Children
D002675	Child, Preschool	A child between the ages of 2 and 5.	Children, Preschool,Preschool Child,Preschool Children
D004354	Drug Screening Assays, Antitumor	Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals.	Anticancer Drug Sensitivity Tests,Antitumor Drug Screens,Cancer Drug Tests,Drug Screening Tests, Tumor-Specific,Dye Exclusion Assays, Antitumor,Anti-Cancer Drug Screens,Antitumor Drug Screening Assays,Tumor-Specific Drug Screening Tests,Anti Cancer Drug Screens,Anti-Cancer Drug Screen,Antitumor Drug Screen,Cancer Drug Test,Drug Screen, Anti-Cancer,Drug Screen, Antitumor,Drug Screening Tests, Tumor Specific,Drug Screens, Anti-Cancer,Drug Screens, Antitumor,Drug Test, Cancer,Drug Tests, Cancer,Screen, Anti-Cancer Drug,Screen, Antitumor Drug,Screens, Anti-Cancer Drug,Screens, Antitumor Drug,Test, Cancer Drug,Tests, Cancer Drug,Tumor Specific Drug Screening Tests
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000293	Adolescent	A person 13 to 18 years of age.	Adolescence,Youth,Adolescents,Adolescents, Female,Adolescents, Male,Teenagers,Teens,Adolescent, Female,Adolescent, Male,Female Adolescent,Female Adolescents,Male Adolescent,Male Adolescents,Teen,Teenager,Youths
D000328	Adult	A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available.	Adults
D013866	Thioguanine	An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia.	6-Thioguanine,2-Amino-6-Purinethiol,Lanvis,Tabloid,Thioguanin-GSK,Thioguanine Anhydrous,Thioguanine Hemihydrate,Thioguanine Monosodium Salt,Thioguanine Tabloid,Tioguanina Wellcome,Tioguanine,2 Amino 6 Purinethiol,6 Thioguanine,Anhydrous, Thioguanine,Thioguanin GSK,ThioguaninGSK
D013997	Time Factors	Elements of limited time intervals, contributing to particular results or situations.	Time Series,Factor, Time,Time Factor
D014407	Tumor Cells, Cultured	Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.	Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured