32P-analysis of DNA adducts in somatic and reproductive tissues of @entity35 treated with the anticancer antibiotic, XXXX .

@entity1 @entity2036 @entity5 @entity1138 @entity2774 @entity5536 @entity1139 @entity5538 @entity35 @entity73103 @entity6244
@entity1138 ( @entity1139 ) is a clinically used drug with mutagenic and antitumor activities, presumably elicited through its covalent binding to DNA, however, little is known about @entity1139 binding to DNA in vivo. @entity73103 -postlabeling method that does not require radiolabeled test compounds was employed here to study the formation of DNA adducts in somatic and reproductive tissues of @entity35 24 h after an i.p. dose of 9 mg/kg @entity1139 . Among 14 tissues studied in female @entity35 , @entity1139 -DNA adduct levels were within a 2-fold range in 11 tissues, i.e. bladder, colon, esophagus, heart, kidney, liver, lung, ovary, pancreas, small intestine and stomach (minimum levels of 9.6-21.9 adducts per 10(7) N). Three other tissues, i.e. brain, spleen and thymus, exhibited lower adduct levels (0.2 5.4 and 1.4 adducts, respectively, per 10(7) N). Liver DNA adduct levels were 32% lower in male than in female @entity35 . Testicular DNA contained 2.5 adducts per 10(7) N, i.e. 5.3 times less than ovarian DNA. 32P-labeled adduct patterns were qualitatively similar among the different tissues and consisted of 10 adducts, one of which comprised 71 (+/- 5)% of the total. All these adducts were chromatographically identical to adducts formed by the reaction of chemically reduced @entity1139 with DNA in vitro, demonstrating that metabolic activation of @entity1139 occurred via reduction. Using homopolydeoxyribonucleotides modified with @entity1139 , in vivo adducts were shown to be mostly (greater than 90%) @entity2774 derivatives and small amounts of @entity5536 , @entity5538 and @entity6244 products. Most of the adducts appeared to be monofunctional derivatives of DNA @entity2036 . Dose-dependent @entity1139 -DNA adduct formation was determined in @entity35 liver over an 82-fold range of @entity1139 administered (0.11-9.0 mg/kg). The lowest dose level studied was 4.5 times lower than the recommended single dose for @entity1 @entity5 chemotherapy (20 mg/m2). Thus, these results predict that 32P-postlabeling methodology is suitable to monitor and quantify DNA adducts in tissue biopsies of @entity1 receiving @entity1139 chemotherapy.
