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

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.

Table 1.

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

	Control	LG268, 60 mg/kg diet	LG268, 30 mg/kg diet	Erlotinib, 200 mg/kg diet	Erlotinib, 100 mg/kg diet
Analysis of inflated lungs
No. mice/group	16	8	8	8	8
No. tumors/group	252	59	70	88	104
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/group	120	43	43	53	55
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, mm³	250	37.5	38.0	44.5	61.6
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

	Control	LG268, 60 mg/kg diet	LG268, 30 mg/kg diet	Erlotinib, 200 mg/kg diet	Erlotinib, 100 mg/kg diet	MA, 800 mg/kg diet
Analysis of inflated lungs
No. mice/group	23	12	12	12	12	16
No. tumors/group	356	89	144	144	145	146
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/group	184	33	78	76	83	73
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, mm³	559.2	45.3	134.4	131.4	196.0	52.5
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.