Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclophosphamide is used to treat a wide range of human malignancies. However, it is also a known carcinogen associated with induction of therapy-related leukemia and bladder cancer. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), protects cells from the toxic and mutagenic effects of O6-alkylating agents. We report here the contribution of AGT in protecting against the toxic and mutagenic effects of cyclophosphamide. CHO cells transduced with wild-type human AGT (CHO(AGT)) and pcDNA3 (CHOpcDNA3) were treated with activated cyclophosphamide derivatives, 4-hydroperoxycyclophosphamide (4-HC), 4-hydroperoxydidechlorocyclophosphamide (4-HDC), a progenitor of acrolein, and phosphoramide mustard (PM). The results show that CHO(AGT) is 7- or 20-fold less sensitive to the toxic effects of 30 microM 4-HC or 300 microM 4-HDC, respectively, than CHOpcDNA3 cells as measured by cell survival using a colony-forming assay. CHO(AGT) cells treated with 20 microM 4-HC or 200 microM 4-HDC produced 4- or 7-fold lower mutation frequency as measured at the HPRT locus than CHOpcDNA3 cells treated with the same dose of drugs. At 30 microM acrolein, the cell survival for CHO(AGT) was 30% compared with 18.7% for CHOpcDNA3. The mutation frequency of acrolein at the same dose was 57 mutants/10(6) cells in CHOpcDNA3 compared with no mutants in CHO(AGT). In contrast, CHO(AGT) and CHOpcDNA3 cells treated with PM had similar survival curves and exhibited no difference in mutation frequency. The present study demonstrates that AGT plays an important role in protecting against the toxic and mutagenic effect of cyclophosphamide and suggests that acrolein, not PM, is responsible for generating the toxic and mutagenic lesion(s) protected by the AGT protein.
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PMID:Role of O6-alkylguanine-DNA alkyltransferase in protecting against cyclophosphamide-induced toxicity and mutagenicity. 1039 44

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) protects from toxicity and mutations incurred following alkylating agents by removing O(6)-alkylguanine lesions. Using Mgmt-/- mice, we examined MGMT's role in protecting from in vivo mutations induced by three different alkylating agents, temozolomide (TMZ), 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide. Mutant frequencies were determined in the hypoxanthine-guanine phosphoribosyltransferase gene of splenic T-lymphocytes from C57BL/6 mice (Mgmt+/+ and Mgmt-/-) following TMZ, BCNU or cyclophosphamide. Following TMZ, the mutation frequency was significantly greater in Mgmt-/- mice (5.5 and 9.8 x 10(-6) for 7 and 10 mg/kg TMZ, respectively) compared with vehicle-treated mice (1.0 x 10(-6), P <or= 0.05). In contrast, TMZ-induced mutations were not increased over vehicle in Mgmt+/+ mice. The mutation frequency of mice treated with BCNU (7.5 mg/kg) was the same regardless of Mgmt status. Similarly, pretreatment of Mgmt+/+ mice with 30 mg/kg O(6)-benzylguanine, a potent inactivator of MGMT, prior to BCNU (15 mg/kg) did not result in significantly more mutations than mice treated with BCNU alone. Following cyclophosphamide, mutation frequencies significantly increased from 1.8 x 10(-6) in control-treated mice to 12.9 x 10(-6) in Mgmt+/+ and 18.1 x 10(-6) in Mgmt-/- mice, although the difference in Mgmt-/- compared with Mgmt+/+ was not significant. Acrolein and chloroacetaldehyde, metabolites of cyclophosphamide, were not mutagenic in Mgmt+/+ and Mgmt-/- mice. These results demonstrate that MGMT significantly protects against in vivo TMZ-induced mutations and that MGMT deficiency does not result in greater mutation frequency following cyclophosphamide or BCNU compared with wild-type mice.
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PMID:Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice. 1711 24