Development of a dietary formulation of the SHetA2 chemoprevention drug for mice View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12-22

AUTHORS

Doris M. Benbrook, Naveena B. Janakiram, Vishal Chandra, Gopal Pathuri, Venkateshwar Madka, Nicole C. Stratton, Chioniso P. Masamha, Cassadie N. Farnsworth, Lucila Garcia-Contreras, Manolya Kukut Hatipoglu, Stan Lighfoot, Chinthalapally V. Rao

ABSTRACT

Development of cancer chemoprevention compounds requires enhanced consideration for toxicity and route of administration because the target population is healthy. The small molecule drug, SHetA2 (NSC 726189), exhibited in vivo chemoprevention activity and lack of toxicity when administered by oral gavage. Our objective was to determine if a dietary formulation of SHetA2 could achieve effective tissue drug levels without toxicity. C57bl/6 J mice were monitored on modified American Institute of Nutrition (AIN)76A diet mixed with SHetA2 in a 3:1 ratio with Kolliphor HS15, a self-emulsifying drug delivery system (SEDDS) to deliver 37.5, 62.5, 125, 187 or 250 mg SHetA2/kg/day. Blood and tissues were evaluated after 1, 3 and 6 weeks. The 187 mg/kg/day dose was identified as optimal based on achievement of maximum blood and tissue drug levels in the effective micromolar range without evidence of toxicity. The 250 mg/kg/day group exhibited lower drug levels and the highest intestinal drug content suggesting that an upper limit of intestinal absorption had been surpassed. Only this highest dose resulted in liver and kidney function tests that were outside of the normal range, and significant reduction of cyclin D1 protein in normal cervical tissue. SHetA2 reduced cyclin D1 to greater extents in cancer compared to non-cancer cell cultures. Given this differential effect, optimal chemoprevention without toxicity would be expected to occur at doses that reduced cyclin D1 in neoplastic, but not in normal tissues. These findings support further development of SHetA2 as a chemoprevention agent and potential food additive. More... »

PAGES

561-570

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-017-0550-0

DOI

http://dx.doi.org/10.1007/s10637-017-0550-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1099922616

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29273857


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22 schema:description Development of cancer chemoprevention compounds requires enhanced consideration for toxicity and route of administration because the target population is healthy. The small molecule drug, SHetA2 (NSC 726189), exhibited in vivo chemoprevention activity and lack of toxicity when administered by oral gavage. Our objective was to determine if a dietary formulation of SHetA2 could achieve effective tissue drug levels without toxicity. C57bl/6 J mice were monitored on modified American Institute of Nutrition (AIN)76A diet mixed with SHetA2 in a 3:1 ratio with Kolliphor HS15, a self-emulsifying drug delivery system (SEDDS) to deliver 37.5, 62.5, 125, 187 or 250 mg SHetA2/kg/day. Blood and tissues were evaluated after 1, 3 and 6 weeks. The 187 mg/kg/day dose was identified as optimal based on achievement of maximum blood and tissue drug levels in the effective micromolar range without evidence of toxicity. The 250 mg/kg/day group exhibited lower drug levels and the highest intestinal drug content suggesting that an upper limit of intestinal absorption had been surpassed. Only this highest dose resulted in liver and kidney function tests that were outside of the normal range, and significant reduction of cyclin D1 protein in normal cervical tissue. SHetA2 reduced cyclin D1 to greater extents in cancer compared to non-cancer cell cultures. Given this differential effect, optimal chemoprevention without toxicity would be expected to occur at doses that reduced cyclin D1 in neoplastic, but not in normal tissues. These findings support further development of SHetA2 as a chemoprevention agent and potential food additive.
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30 C57BL/6
31 D1
32 D1 protein
33 HS15
34 Institute
35 Kolliphor HS15
36 SHetA2
37 SHetA2 chemoprevention drug
38 SHetA2/
39 absorption
40 achievement
41 activity
42 administration
43 agents
44 blood
45 cancer
46 cancer chemoprevention compounds
47 cell cultures
48 cervical tissue
49 chemoprevention
50 chemoprevention activity
51 chemoprevention agents
52 chemoprevention compounds
53 chemoprevention drugs
54 compounds
55 consideration
56 content
57 culture
58 cyclin D1
59 cyclin D1 protein
60 day dose
61 day group
62 days
63 delivery system
64 development
65 diet
66 dietary formulations
67 differential effects
68 dose
69 doses
70 drug content
71 drug delivery systems
72 drug levels
73 drugs
74 effect
75 effective micromolar range
76 effective tissue drug levels
77 enhanced consideration
78 evidence
79 evidence of toxicity
80 extent
81 findings
82 food
83 formulation
84 function tests
85 further development
86 gavage
87 greater extent
88 group
89 high dose
90 highest intestinal drug content
91 intestinal absorption
92 intestinal drug content
93 kidney function tests
94 lack
95 lack of toxicity
96 levels
97 limit
98 liver
99 low drug levels
100 maximum blood
101 mice
102 micromolar range
103 molecule drugs
104 non-cancer cell cultures
105 normal cervical tissues
106 normal range
107 normal tissues
108 nutrition
109 objective
110 optimal chemoprevention
111 oral gavage
112 population
113 potential food
114 protein
115 range
116 ratio
117 reduction
118 route
119 route of administration
120 self-emulsifying drug delivery systems
121 significant reduction
122 small molecule drugs
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125 test
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128 toxicity
129 upper limit
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