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Dose-response on the chemopreventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice.

Guillermo RF, Zhang X, Kaushik RS, Zeman D, Ahmed SA, Khalifa S, Fahmy H, Dwivedi C - Mar Drugs (2012)

Bottom Line: Weight gain and any signs of toxicity were also closely monitored.The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose.The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA. Ruth.Guillermo@sdstate.edu

ABSTRACT
Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 μg SD applied topically and 180 mJ/cm(2) UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm(2). This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into five groups. The control group was topically treated with 200 μL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 μg, 45 μg, and 60 μg dissolved in 200 μL of acetone) 1 h before UVB radiation (30 mJ/cm(2)). The last group of animals received 60 μg SD/200 μL acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were also closely monitored. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment. The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose. SD reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD application without UVB exposure has no effect on the structure of skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

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Effects of SD treatment on tumor incidence in SKH-1 mice. SD pre-treatment did not affect the incidence of tumors (n=20 per group). By the 13th week, one animal from the 30 μg/dose group developed one tumor. During the week 17th, animals from the control group started developing tumors, while tumors started appearing by the 18th week in the animals treated with 45 and 60 μg/dose. By the 25th week, the incidence for all groups ranged from 95% to 100%. The group treated with 60 μg/dose of SD and no UVB exposure, did not develop tumors at any time during the experiment.
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marinedrugs-10-02111-f002: Effects of SD treatment on tumor incidence in SKH-1 mice. SD pre-treatment did not affect the incidence of tumors (n=20 per group). By the 13th week, one animal from the 30 μg/dose group developed one tumor. During the week 17th, animals from the control group started developing tumors, while tumors started appearing by the 18th week in the animals treated with 45 and 60 μg/dose. By the 25th week, the incidence for all groups ranged from 95% to 100%. The group treated with 60 μg/dose of SD and no UVB exposure, did not develop tumors at any time during the experiment.

Mentions: Tumor incidence is defined as the percentage of mice bearing at least one tumor on the treated area. The effects of SD treatment on the tumor incidence are shown in Figure 2. By the 18th week at least one animal in all groups presented at least one tumor, except the group not exposed to UVB. By the end of the experiment, at week 27, all UVB-exposed groups had a tumor incidence rate between 95%–100%. Except for the one animal that developed one tumor at week 13th into the protocol, the chronology of the tumorigenesis is consistent with previous reports from our laboratory, using a similar UVB dose/protocol in SKH-1 mice [29,30]. The reasons why that one animal in the 30 μg/dose group developed one tumor earlier in the experiment can be explained by the fact that they are outbred animals and may have different immune response when insulted by the UVB radiation. As with people, some individuals may be more susceptible to the UVB skin damage, having less repair mechanism, less natural apoptotic response or other factors that we did not explore in this particular experiment. Results showed that SD pre-treatment in concentrations of 30, 45, 60 μg/dose did not have significant (P < 0.05) effects on the incidence of tumors throughout the experiment.


Dose-response on the chemopreventive effects of sarcophine-diol on UVB-induced skin tumor development in SKH-1 hairless mice.

Guillermo RF, Zhang X, Kaushik RS, Zeman D, Ahmed SA, Khalifa S, Fahmy H, Dwivedi C - Mar Drugs (2012)

Effects of SD treatment on tumor incidence in SKH-1 mice. SD pre-treatment did not affect the incidence of tumors (n=20 per group). By the 13th week, one animal from the 30 μg/dose group developed one tumor. During the week 17th, animals from the control group started developing tumors, while tumors started appearing by the 18th week in the animals treated with 45 and 60 μg/dose. By the 25th week, the incidence for all groups ranged from 95% to 100%. The group treated with 60 μg/dose of SD and no UVB exposure, did not develop tumors at any time during the experiment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475277&req=5

marinedrugs-10-02111-f002: Effects of SD treatment on tumor incidence in SKH-1 mice. SD pre-treatment did not affect the incidence of tumors (n=20 per group). By the 13th week, one animal from the 30 μg/dose group developed one tumor. During the week 17th, animals from the control group started developing tumors, while tumors started appearing by the 18th week in the animals treated with 45 and 60 μg/dose. By the 25th week, the incidence for all groups ranged from 95% to 100%. The group treated with 60 μg/dose of SD and no UVB exposure, did not develop tumors at any time during the experiment.
Mentions: Tumor incidence is defined as the percentage of mice bearing at least one tumor on the treated area. The effects of SD treatment on the tumor incidence are shown in Figure 2. By the 18th week at least one animal in all groups presented at least one tumor, except the group not exposed to UVB. By the end of the experiment, at week 27, all UVB-exposed groups had a tumor incidence rate between 95%–100%. Except for the one animal that developed one tumor at week 13th into the protocol, the chronology of the tumorigenesis is consistent with previous reports from our laboratory, using a similar UVB dose/protocol in SKH-1 mice [29,30]. The reasons why that one animal in the 30 μg/dose group developed one tumor earlier in the experiment can be explained by the fact that they are outbred animals and may have different immune response when insulted by the UVB radiation. As with people, some individuals may be more susceptible to the UVB skin damage, having less repair mechanism, less natural apoptotic response or other factors that we did not explore in this particular experiment. Results showed that SD pre-treatment in concentrations of 30, 45, 60 μg/dose did not have significant (P < 0.05) effects on the incidence of tumors throughout the experiment.

Bottom Line: Weight gain and any signs of toxicity were also closely monitored.The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose.The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA. Ruth.Guillermo@sdstate.edu

ABSTRACT
Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 μg SD applied topically and 180 mJ/cm(2) UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm(2). This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into five groups. The control group was topically treated with 200 μL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 μg, 45 μg, and 60 μg dissolved in 200 μL of acetone) 1 h before UVB radiation (30 mJ/cm(2)). The last group of animals received 60 μg SD/200 μL acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were also closely monitored. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment. The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose. SD reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD application without UVB exposure has no effect on the structure of skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects.

Show MeSH
Related in: MedlinePlus