Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secondary or therapy-related acute myelogenous leukemia (t-AML) is a rare but unfortunate consequence of treatment with certain classes of cytotoxic chemotherapeutic agents or chronic exposure to high concentrations of benzene. Drugs known to produce AML following chemotherapy of primary malignancy are usually alkylating agents or topoisomerase II inhibitors. Both children and adults develop AML following treatment with these classes of antineoplastic drugs. In this review, the effect of age at treatment on a child's susceptibility to developing therapy related AML was investigated. The clinical literature describing pediatric cancer patients treated with cytotoxic chemotherapeutic agents was used to characterize risk factors associated with chemical leukemogenesis in children. As demonstrated in the published literature, the risk of developing AML following chemotherapy is not reliably correlated with the age of the pediatric patient. There is no consistent evidence that indicates that younger children will be at increased risk; in fact, some studies suggest that younger children might actually display a decreased susceptibility. The age dependency of treatment-related malignancies (all types) in children appears to vary considerably with the type of secondary neoplasm in question. For example, secondary solid tumors such as breast, central nervous system (CNS), bone, and thyroid cancer are highly dependent on the age of the patient at time of diagnosis and treatment; in contrast, an age dependency for t-AML risk was not observed in these same patient populations. Predictably, the induction of t-AML in children follows a rational dose-response relationship, with increasing doses of chemotherapy resulting in greater risk. Recent U.S. Environmental Protection Agency (EPA) cancer risk assessment guidance recommends a default assumption that children are inherently up to 10-fold more sensitive than adults to carcinogen exposures. Available scientific and medical literature does not support the hypothesis that children necessarily possess an increased risk of developing AML following leukemogenic chemical exposure.
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PMID:Is age an independent risk factor for chemically induced acute myelogenous leukemia in children? 1768 25

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APH-induced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication.
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PMID:DNA topoisomerases participate in fragility of the oncogene RET. 2404 Apr 17