8-hydroxyguanine and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Oxidative DNA damage caused by reactive oxygen species can produce 8-oxoguanine (8-oxoG) in DNA, which is misread and leads to G:C→T:A transversions. This can be carcinogenic. Repair of 8-oxoG by the base excision repair pathway involves the activity of human 8-oxoG DNA glycosylase 1 (hOGG1). Accumulating evidence suggests that the hOGG1 Ser326Cys polymorphism affects the activity of hOGG1 and might serve as a genetic marker for susceptibility to several cancers. To determine whether this polymorphism is associated with risk of childhood acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped the hOGG1 Ser326Cys polymorphism (rs1052133) in a case-control study including 415 cases and 511 controls. We found that there was a significant difference in the genotype distributions of the hOGG1 Ser326Cys polymorphism between cases and controls (P = 0.046), and the combined genotypes Ser/Ser and Ser/Cys were associated with a statistically significantly decreased risk of ALL (adjusted odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.49-0.88, P = 0.005). Furthermore, we found a decreased risk for high risk ALL (adjusted OR = 0.60, 95% CI = 0.40-0.88, P = 0.005), low risk ALL (adjusted OR = 0.68, 95% CI = 0.47-0.99, P = 0.042), and B-phenotype ALL (adjusted OR = 0.63, 95% CI = 0.46-0.86, P = 0.003) among children with the Ser/Ser and Ser/Cys genotypes. Our results suggest that the hOGG1 Ser326Cys polymorphism is associated with susceptibility to childhood ALL in a Chinese population.

Topics: Adolescent; Case-Control Studies; Child; Child, Preschool; China; DNA Damage; DNA Glycosylases; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Guanine; Humans; Infant; Male; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reactive Oxygen Species

Anthracycline derivatives such as doxorubicin are part of many chemotherapeutic regimens and reach peak plasma concentrations of 5 microM. We investigated the cytotoxic mechanisms of various doxorubicin concentrations in MOLT-4 ALL-cells. Concentrations of up to 100 microM doxorubicin achieved similar cytotoxic effects in cultures of MOLT-4 cells, but acted via different mechanisms. Doxorubicin induced apoptosis (maximum effect at 1 microM), which was dependent on RNA synthesis and involved oxidative stress. Concentrations higher than 3 microM did not induce apoptosis, but significantly inhibited RNA synthesis. DNA strand breaks in MOLT-4 cells occurred in the presence of 1 to 5 microM doxorubicin to a similar extent, but showed a dose-dependence at higher concentrations. There was no GC/MS-detectable oxidation of DNA bases in apoptotic cells and only 1 out of 13 DNA base oxidation products, 8-hydroxyguanine, increased significantly in the presence of as much as 100 microM doxorubicin. These results suggest that at pharmacologically relevant concentrations apoptosis and not oxidative DNA damage is the main killing mechanism of doxorubicin against ALL-cells.

Topics: Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Butylated Hydroxyanisole; Cell Division; Cell Line; Cell Nucleus; DNA Damage; DNA, Neoplasm; Doxorubicin; Guanine; Humans; Kinetics; Oxidative Stress; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Neoplasm; Tumor Cells, Cultured; Uridine