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Title: Identifying Efficacious Approaches to Chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a Mouse Model of Transplacental Carcinogenesis

Abstract

The carcinogenic potential of dibenzo[a,l]pyrene (DBP) has been well characterized in numerous animal models. We have previously documented that a single dose of 15 mg/Kg DBP to pregnant mice late in gestation (GD 17) produces an aggressive T-cell lymphoma as well as lung and liver cancer in offspring. The current study examines the chemopreventative properties of chlorophyllin (CHL) and chlorophyll (Chl) in this transplacental carcinogenesis model. Pregnant B6129SF1 females, bred to 129S1/SvIm males, received purified diets incorporated with either 2000 ppm CHL, 2000 ppm Chl, or 10% freeze-dried spinach beginning at gestation day 9. Lymphoma-dependent mortality was not significantly altered by maternal consumption of any of the diet and little effect on lung tumor burden in mice surviving to 10 months of age was observed. However, co-administration of CHL at 380 mg/Kg with DBP by gavage (molar ratio of 10:1, CHL:DBP) provided significant protection against DBP initiated carcinogenesis. Offspring born to dams receiving CHL co-gavaged with DBP exhibited markedly fewer lymphoma-dependent mortalities (p< 0.001). The degree of protection by CHL, compared to controls dosed with DBP in tricaprylin (TCP) as the vehicle, were less marked, but still significant. Co-administration of CHL (TCP as vehicle) also reduced lung tumor multiplicity inmore » mice by approximately 50% and this was observed throughout the study (p< 0.005). This is the first demonstration that CHL can provide potent chemoprotection in a transplacental carcinogenesis model and supports a mechanism involving complex-mediated reduction of carcinogen uptake.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
950725
Report Number(s):
PNNL-SA-60493
Journal ID: ISSN 0143-3334; CRNGDP; TRN: US200910%%302
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Carcinogenesis, 30(2):315-320; Journal Volume: 30; Journal Issue: 2
Country of Publication:
United States
Language:
English
Subject:
13 HYDRO ENERGY; ANIMALS; CARCINOGENESIS; CARCINOGENS; CHLOROPHYLL; DAMS; DIET; FEMALES; LIVER; LUNGS; LYMPHOMAS; MALES; MICE; MORTALITY; MULTIPLICITY; NEOPLASMS; PROGENY; SPINACH

Citation Formats

Castro, David J., Lohr, Christiane V., Fischer, Kay A., Waters, Katrina M., Webb-Robertson, Bobbie-Jo M., Dashwood, Roderick H., Bailey, George S., and Williams, David E. Identifying Efficacious Approaches to Chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a Mouse Model of Transplacental Carcinogenesis. United States: N. p., 2009. Web.
Castro, David J., Lohr, Christiane V., Fischer, Kay A., Waters, Katrina M., Webb-Robertson, Bobbie-Jo M., Dashwood, Roderick H., Bailey, George S., & Williams, David E. Identifying Efficacious Approaches to Chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a Mouse Model of Transplacental Carcinogenesis. United States.
Castro, David J., Lohr, Christiane V., Fischer, Kay A., Waters, Katrina M., Webb-Robertson, Bobbie-Jo M., Dashwood, Roderick H., Bailey, George S., and Williams, David E. Sun . "Identifying Efficacious Approaches to Chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a Mouse Model of Transplacental Carcinogenesis". United States. doi:.
@article{osti_950725,
title = {Identifying Efficacious Approaches to Chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a Mouse Model of Transplacental Carcinogenesis},
author = {Castro, David J. and Lohr, Christiane V. and Fischer, Kay A. and Waters, Katrina M. and Webb-Robertson, Bobbie-Jo M. and Dashwood, Roderick H. and Bailey, George S. and Williams, David E.},
abstractNote = {The carcinogenic potential of dibenzo[a,l]pyrene (DBP) has been well characterized in numerous animal models. We have previously documented that a single dose of 15 mg/Kg DBP to pregnant mice late in gestation (GD 17) produces an aggressive T-cell lymphoma as well as lung and liver cancer in offspring. The current study examines the chemopreventative properties of chlorophyllin (CHL) and chlorophyll (Chl) in this transplacental carcinogenesis model. Pregnant B6129SF1 females, bred to 129S1/SvIm males, received purified diets incorporated with either 2000 ppm CHL, 2000 ppm Chl, or 10% freeze-dried spinach beginning at gestation day 9. Lymphoma-dependent mortality was not significantly altered by maternal consumption of any of the diet and little effect on lung tumor burden in mice surviving to 10 months of age was observed. However, co-administration of CHL at 380 mg/Kg with DBP by gavage (molar ratio of 10:1, CHL:DBP) provided significant protection against DBP initiated carcinogenesis. Offspring born to dams receiving CHL co-gavaged with DBP exhibited markedly fewer lymphoma-dependent mortalities (p< 0.001). The degree of protection by CHL, compared to controls dosed with DBP in tricaprylin (TCP) as the vehicle, were less marked, but still significant. Co-administration of CHL (TCP as vehicle) also reduced lung tumor multiplicity in mice by approximately 50% and this was observed throughout the study (p< 0.005). This is the first demonstration that CHL can provide potent chemoprotection in a transplacental carcinogenesis model and supports a mechanism involving complex-mediated reduction of carcinogen uptake.},
doi = {},
journal = {Carcinogenesis, 30(2):315-320},
number = 2,
volume = 30,
place = {United States},
year = {Sun Feb 01 00:00:00 EST 2009},
month = {Sun Feb 01 00:00:00 EST 2009}
}
  • Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at themore » 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.« less
  • Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence inmore » mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.« less
  • Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies weremore » well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and investigating a potential transplacental component of the human carcinogenic response to arsenic should be a research priority.« less
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