Eppley Institute for Research in Cancer and Allied Diseases

About: Eppley Institute for Research in Cancer and Allied Diseases is a based out in . It is known for research contribution in the topics: Pancreatic cancer & Cancer. The organization has 965 authors who have published 1396 publications receiving 58994 citations.

Catechol estrogen conjugates and DNA adducts in the kidney of male Syrian golden hamsters treated with 4-hydroxyestradiol: potential biomarkers for estrogen-initiated cancer.

Abstract: Formation of depurinating adducts by reaction of catechol estrogen-3,4-quinones with DNA was proposed to be a tumor initiating event by estrogens [E.L. Cavalieri et al. (1997) Proc. Natl Acad. Sci. USA, 94, 10937-10942]. Under estrogenic imbalance, oxidation of catechol estrogens to quinones may compete with their detoxification by protective enzymes. The quinones formed can be detoxified by reaction with glutathione (GSH) or can covalently bind to DNA. To provide more support for this hypothesis, we developed a method to identify and quantify GSH, cysteine (Cys) and N-acetylCys conjugates of 4-hydroxyestrogens (4-OHE) in the kidneys of male Syrian hamsters treated with 4-hydroxyestradiol (4-OHE2) by intraperitoneal injection. The highest level of conjugates was observed 1 h after treatment, and almost none was detected after 24 h. Dose-response studies indicated conjugate formation after treatment with 0.5 micromol of 4-OHE2/100 g body weight, and formation increased up to a treatment level of 12 micromol/100 g body weight. GSH, Cys and N-acetylCys conjugates of 4-OHE were identified in the picomole range by high-performance liquid chromatography (HPLC) with multichannel electrochemical detection and confirmed by HPLC/tandem mass spectrometry. Treatment of tissue homogenates with beta-glucuronidase/sulfatase at 37 degrees C for 6 h before extraction resulted in a 12- to 20-fold increase in Cys conjugates from picomole to nanomole levels. Similar enhancement was observed by just incubating the tissue at 37 degrees C for 6 h. Evidence for the 4-OHE-1-N7Gua depurinating adducts was obtained by mass spectrometry. We conclude that GSH and Cys conjugates of the 4-OHE and the 4-OHE-N7Gua adducts can be utilized as biomarkers to detect estrogenic imbalance and potential susceptibility to tumor initiation.

Influence of Diet and Calorie Restriction on the Initiation and Promotion of Skin Carcinogenesis in the Sencar Mouse Model

Abstract: Diets were restricted to 60% of the intake of the control mice by feeding less diet (total diet restriction, TDR) or by feeding fewer calories from fat and carbohydrate (calorie restriction, CR) during the initiation or promotion phases of skin tumorigenesis in female SENCAR mice. Skin cancer was initiated by topical treatment with 10 nmol of 7,12-dimethylbenzanthracene in acetone and promoted by twice weekly treatments with 12-O-tetradecanoylphorbol-13-acetate in acetone for 20 wk. Dietary restriction preceding and during 7,12-dimethylbenzanthracene treatment did not influence skin papilloma or carcinoma yield. Papilloma incidence and the number of papillomas per effective mouse were reduced in mice restricted by both TDR and CR protocols during and following promotion with 12-O-tetradecanoylphorbol-13-acetate. Papilloma size was reduced at experimental wk 16 and 20 in both TDR and CR groups fed these diet regimens during promotion. However, by wk 28 and 32, papilloma sizes were similar in the control and TDR groups, and smaller papillomas were observed only in the CR group. The average carcinoma latency was extended by 26% in the groups restricted during promotion, and incidence was reduced in both groups. The reduction, however, was statistically significant only in the CR group. Body weight gain was reduced during the times when dietary restriction was enforced, and in a short-term study, both restricted diet treatments reduced the percentage of carcass protein.

Groove- and sequence-selective alkylation of DNA by sulfonate esters tethered to lexitropsins

Abstract: A series of sulfonate esters that are attached to a noncationic minor-groove-binding N-methylpyrrole dipeptide (Lex) related to netrospin have been synthesized. The compounds prepared differ in two respects: (1) the length [(CH2)2 vs (CH2)8] of the tether between the DNA affinity binding portion of the molecule and the sulfonate ester and (2) whether a methyl group [MeOSO2(CH2)n-Lex] or the dipeptide including the aliphatic tether [MeSO2O(CH2)n-Lex] is covalently transferred to the DNA. The DNA-cleavage patterns of these bimolecular alkylating compounds have been mapped in 32P-end-labeled restriction fragments using neutral thermal hydrolysis and alkali treatment to expose single-strand breaks at bases with thermally labile modifications. In contrast to the alkylation of DNA by simple alkyl alkanesulfonate esters, that predominantly yield major-groove alkylation at N7-guanine, the modification of DNA by MeOSO2(CH2)n-Lex and MeSO2O(CH2)n-Lex occurs primarily at N3-adenine residues associated with previously footprinted Lex DNA affinity binding regions. The ratio for the formation of N3-methyladenine (minor groove) to N7-methylguanine (major groove) in calf thymus DNA is 1:7 for dimethyl sulfate, while only the former adenine product is observed with MeSO2O(CH2)n-Lex indicating the change in groove specificity. DNA cleavage by MeOSO2(CH2)n-Lex and MeSO2O(CH2)n-Lex is efficiently inhibited by the coaddition of distamycin; however, only the DNA damage generated by the latter is blocked by NaCl. As expected, increasing the length of the (CH2)n tether from n = 2 to n = 8 moves the alkylation site by 1-2 base pairs further from the affinity binding domain. Finally, a comparison of the methylation patterns of MeOSO2(CH2)n-Lex as a function of tether length provides an insight into Lex sequence and orientational preferences.