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Molecular Cancer Therapeutics
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Research Articles: Therapeutics, Targets, and Development

The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis

Karen Liby, Candice C. Black, Darlene B. Royce, Charlotte R. Williams, Renee Risingsong, Mark M. Yore, Xi Liu, Tadashi Honda, Gordon W. Gribble, William W. Lamph, Thomas A. Sporn, Ethan Dmitrovsky and Michael B. Sporn
Karen Liby
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Candice C. Black
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Darlene B. Royce
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Charlotte R. Williams
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Renee Risingsong
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Mark M. Yore
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Xi Liu
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Tadashi Honda
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Gordon W. Gribble
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William W. Lamph
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Thomas A. Sporn
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Ethan Dmitrovsky
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Michael B. Sporn
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DOI: 10.1158/1535-7163.MCT-08-0023 Published May 2008
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    Figure 1.

    Histopathology of preinvasive and advanced lesions and quantification of the histopathology of a serial sacrifice study. Female A/J mice were injected i.p. with two doses of vinyl carbamate (0.32 mg/mouse), 1 week apart. A, representative pictures (×100 and ×400) of a preinvasive lesion, that is, atypical adenomatous hyperplasia, in the lung of a mouse 4 wk after the final injection of carcinogen (top), a high-grade tumor (middle), and a tumor invading into a bronchus (bottom). B, diameter of tumors on slides (six slides per time point) was measured, and the tumors were scored for both histologic and nuclear morphology as described previously (13). Tumors were assigned low grade (low histologic and nuclear grade), medium grade (low histologic and high nuclear grade), or high grade (high histologic and nuclear grade), and the percentages of TTV per grade are shown for weeks 6 to 28.

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    Figure 2.

    Gross appearance of lungs at necropsy and geminin immunohistochemistry. A, representative pictures of lungs from four mice per experimental group after 20 wk on diet. Full details of tumor size and histopathology are described in Table 2. B, geminin staining in the lung or tumor of mice fed LG268 or control diet for 20 wk. Arrows, positive cells.

Tables

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  • Table 1.

    LG268 and erlotinib prevent lung carcinogenesis in A/J mice injected with vinyl carbamate, 14 wk on diet

    ControlLG268, 60 mg/kg dietLG268, 30 mg/kg dietErlotinib, 200 mg/kg dietErlotinib, 100 mg/kg diet
    Analysis of inflated lungs
        No. mice/group168888
        No. tumors/group252597088104
        No. tumors/mouse (% control)15.8 ± 1.0 (100)7.4 ± 1.3* (47)8.8 ± 1.1* (56)11.0 ± 1.8† (70)13.0 ± 1.5 (82)
        No. tumors ≤0.5 mm (% of total tumors)7 (3)13 (22)†10 (14)16 (18)†10 (10)
        No. tumors >1 mm (% of total tumors)49 (19)4 (7)†2 (3)†2 (2)†11 (10)
    Analysis of histopathology
        Total no. tumors/group12043435355
        Average no. tumors/slide (% control)3.9 ± 0.3 (100)2.9 ± 0.5† (74)2.7 ± 0.3† (69)3.3 ± 0.4 (85)3.4 ± 0.3 (89)
        TTV, mm325037.538.044.561.6
        Average tumor size, mm3 (% control)2.1 ± 0.3 (100)0.9 ± 0.2† (42)0.9 ± 0.2† (42)0.8 ± 0.1† (40)1.1 ± 0.1 (54)
        Average tumor burden, mm3/slide (% control)8.1 ± 1.5 (100)2.5 ± 0.6† (31)2.4 ± 0.5† (29)2.8 ± 0.6† (34)3.9 ± 0.6 (48)
        Total no. low-grade tumors (%)20 (17)22 (51)*20 (46)*17 (32)†13 (23)
        Total no. medium-grade tumors (%)25 (21)9 (21)12 (28)16 (30)24 (44)†
        Total no. high-grade tumors (%)75 (62)12 (28)*11 (26)*20 (38)†18 (33)*
    • NOTE: Female A/J mice were injected i.p. with two doses of vinyl carbamate (0.32 mg/mouse), 1 wk apart. One week after the final injection with the carcinogen, mice were fed compounds in diet for 14 wk. Mean ± SE.

    • ↵* P < 0.001 versus control.

    • ↵† P < 0.05 versus control.

  • Table 2.

    LG268 and CDDO-MA are more potent than erlotinib for preventing lung carcinogenesis in A/J mice injected with vinyl carbamate, 20 wk on diet

    ControlLG268, 60 mg/kg dietLG268, 30 mg/kg dietErlotinib, 200 mg/kg dietErlotinib, 100 mg/kg dietMA, 800 mg/kg diet
    Analysis of inflated lungs
        No. mice/group231212121216
        No. tumors/group35689144144145146
        No. tumors/mouse (% control)15.5 ± 1.0 (100)7.4 ± 1.0* (48)12 ± 0.6 (77)12.0 ± 1.1 (77)12 ± 0.9 (78)9.1 ± 0.7* (59)
        No. tumors ≤0.5 mm (% of total tumors)14 (4)25 (28)*18 (13)19 (13)7 (5)63 (43)*
        No. tumors >1 mm (% of total tumors)103 (29)6 (7)*19 (13)10 (7)*30 (21)1 (1)*
    Analysis of histopathology
        Total no. tumors/group1843378768373
        Average no. tumors/slide (% control)4.2 ± 0.3 (100)1.4 ± 0.3* (33)3.3 ± 0.4 (78)3.2 ± 0.3 (76)3.5 ± 0.3 (83)2.3 ± 0.3* (55)
        TTV, mm3559.245.3134.4131.4196.052.5
        Average tumor size, mm3 (% control)3.0 ± 0.3 (100)1.4 ± 0.4* (45)1.7 ± 0.4* (57)1.7 ± 0.4* (57)2.4 ± 0.5 (78)0.7 ± 0.1* (24)
        Average tumor burden, mm3/slide (% control)12.7 ± 1.5 (100)1.9 ± 0.4* (15)5.6 ± 1.2* (44)5.5 ± 1.0* (43)8.2 ± 1.0 (64)1.6 ± 0.3* (13)
        No. low-grade tumors (%)25 (13)3 (9)18 (23)23 (30)*14 (17)35 (48)*
        No. medium-grade tumors (%)51 (28)20 (61)*27 (35)30 (40)27 (32)20 (27)
        No. high-grade tumors (%)108 (59)10 (30)*33 (42)*23 (30)*42 (51)18 (25)*
    • NOTE: Female A/J mice were injected i.p. with two doses of vinyl carbamate (0.32 mg/mouse), 1 wk apart. One week after the final injection with the carcinogen, mice were fed compounds in diet for 20 wk. Mean ± SE.

    • ↵* P < 0.05 versus control.

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Molecular Cancer Therapeutics: 7 (5)
May 2008
Volume 7, Issue 5
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The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis
Karen Liby, Candice C. Black, Darlene B. Royce, Charlotte R. Williams, Renee Risingsong, Mark M. Yore, Xi Liu, Tadashi Honda, Gordon W. Gribble, William W. Lamph, Thomas A. Sporn, Ethan Dmitrovsky and Michael B. Sporn
Mol Cancer Ther May 1 2008 (7) (5) 1251-1257; DOI: 10.1158/1535-7163.MCT-08-0023

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The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis
Karen Liby, Candice C. Black, Darlene B. Royce, Charlotte R. Williams, Renee Risingsong, Mark M. Yore, Xi Liu, Tadashi Honda, Gordon W. Gribble, William W. Lamph, Thomas A. Sporn, Ethan Dmitrovsky and Michael B. Sporn
Mol Cancer Ther May 1 2008 (7) (5) 1251-1257; DOI: 10.1158/1535-7163.MCT-08-0023
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