Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivoi

被引:70
作者
Nyati, MK
Maheshwari, D
Hanasoge, S
Sreekumar, A
Rynkiewicz, SD
Chinnaiyan, AM
Leopold, WR
Ethier, SP
Lawrence, TS
机构
[1] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA
[3] Pfizer Global Res & Dev, Ann Arbor Labs, Ann Arbor, MI USA
关键词
D O I
10.1158/1078-0432.CCR-1041-03
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Overexpression of the ErbB family of receptor tyrosine kinases has been associated with uncontrolled growth of many tumor types and, therefore, presents a promising molecular target for cancer therapy. CI-1033 is a small molecule tyrosine kinase inhibitor that differs from other 4-anilinoquinazolines by being a pan ErbB (instead of epidermal growth factor receptor-specific) irreversible (instead of reversible) inhibitor. Therefore, we investigated the antitumor effect of CI-1033 alone and in combination with ionizing radiation in vitro and in vivo. Experimental Design: We selected three human colon carcinoma cell-lines (LoVo, Caco-2, which express activated epidermal growth factor receptor and ErbB-2 family members, and SW620, which does not), and analyzed the effects of CI-1033 both in vitro and in vivo. For in vivo studies LoVo and Caco-2 cells were implanted s.c. in the flank of nude mice. After the tumor reached similar to100 mm(3), treatment was initiated with 20 mg/kg of CI-1033 (orally once daily x 5 for 3 successive weeks), radiation treatment (a total of 30 Gy given in 2 Gy once daily x 5 for 3 successive weeks), or a combination of both CI-1033 and radiation treatment. Results: We found that exposure of LoVo and Caco-2, but not SW620 cells, to CI-1033 in the range of 1-3 muM could inhibit constitutive signaling by tyrosine kinases, arrest cell growth, inhibit cells in G(1), stimulate expression of p53, and induce apoptosis. The inhibition of cell growth by CI-1033 seemed to produce only minimal radiosensitization in LoVo and Caco-2 cells. In contrast, the combination of CI-1033 and radiation produced significant (P < 0.0005 and P = 0.0002, respectively) and prolonged suppression of tumor growth in both the tumor types when compared with either treatment alone. Conclusions: These findings suggest that CI-1033 can increase the effectiveness of radiation therapy. The extent of suppression of tyrosine kinase activity by CI-1033, rather than the amount of activity in untreated cells, seemed to be more closely associated with the efficacy of combination treatment.
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页码:691 / 700
页数:10
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