K-ras codon 12 and 61 point mutations in bromodeoxyuridine- and N-nitrosomethylurea-induced rat renal mesenchymal tumors

Calvert, Richard J.; Buzard, Gregory S.; Anisimov, Vladimir N.; Rice, Jerry M.

doi:10.1016/s0304-3835(96)04350-9

Cited by 5 publications

(2 citation statements)

References 14 publications

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“…Overall, K -ras appears to be a weak negative prognostic marker in adenocarcinoma of the lung (24, 25). The major type of K- ras mutation that we report in lung tumors is similar to other reports (26, 27). In the studies presented here, the K- ras wild-type tumors are selectively targeted with the L2G7 neutralizing antibody to human HGF, suggesting that downstream constitutive activation of the ras pathway in K- ras mutant tumors make them more resistant to inhibition that blocks an upstream tyrosine kinase receptor.…”

Section: Discussionsupporting

confidence: 92%

Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis

Stabile

Rothstein

Keohavong

et al. 2008

Molecular Cancer Therapeutics

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The hepatocyte growth factor (HGF)/c-Met signaling pathway is involved in lung tumor growth and progression, and agents that target this pathway have clinical potential for lung cancer treatment. L2G7, a single potent antihuman HGF neutralizing monoclonal antibody, showed profound inhibition of human HGF-induced phosphorylated mitogen-activated protein kinase induction, wound healing, and invasion in lung tumor cells in vitro. Transgenic mice that overexpress human HGF in the airways were used to study the therapeutic efficacy of L2G7 for lung cancer prevention. Mice were treated with the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, over 4 weeks. Beginning at week 3, i.p. treatment with 100 Mg L2G7 or isotype-matched antibody control, 5G8, was initiated and continued through week 15. The mean number of tumors per mouse in the L2G7-treated group was significantly lower than in the control group (1.58 versus 3.19; P = 0.0005). Proliferative index was decreased by 48% (P = 0.013) in tumors from L2G7-treated mice versus 5G8-treated mice, whereas extent of apoptosis was increased in these same tumors by 5-fold (P = 0.0013). Phosphorylated mitogen-activated protein kinase expression was also significantly decreased by 84% in tumors from L2G7-treated mice versus 5G8-treated mice (P = 0.0003).Tumors that arose in HGF transgenic animals despite L2G7 treatment were more likely to contain mutant K-ras, suggesting that targeting the HGF/c-Met pathway may not be as effective if downstream signaling is activated by a K-ras mutation. These preclinical results show that blocking the HGF/c-Met interaction with a single monoclonal antibody delivered systemically can have profound inhibitory effects on development of lung tumors. [Mol Cancer Ther 2008;7(7):1913 -22]

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Section: Discussionsupporting

confidence: 92%

Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis

Stabile

Rothstein

Keohavong

et al. 2008

Molecular Cancer Therapeutics

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“…Nitrosourea compounds including N -methyl- N -nitrosourea (MNU) also possess carcinogenic potency in the kidneys 8 , 9 , and MNU induces renal mesenchymal tumors (RMTs) and nephroblastomas in rats 10 , 11 , 12 . The formation and persistence of DNA adducts, such as O 6 -methylguanine, and K- ras codon 12 and 16 point mutations in renal cortical tubular cells and/or mesenchymal interstitial cells is related to the tumor development induced by alkylating agents 9 , 13 .…”

Section: Introductionmentioning

confidence: 99%

<i>N</i>-Methyl-<i>N </i>-nitrosourea-induced Renal Tumors in Rats: Immunohistochemical Comparison to Human Wilms Tumors

et al. 2013

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N-Methyl-N-nitrosourea (MNU)-induced renal tumors in rats and Wilms tumors in humans were compared. Renal mesenchymal tumors (RMTs) and nephroblastomas (blastemal and epithelial components) in female Lewis rats treated with a single intraperitoneal injection of 50 mg/kg MNU at birth and Wilms tumors (blastemal, epithelial and mesenchymal components) in humans were analyzed for the expression of pancytokeratin (CK), vimentin, p63, α-smooth muscle actin (SMA), desmin, S-100, CD57, CD117/c-kit, Wilms tumor 1 protein (WT1) and β-catenin. The mesenchymal components of rat RMTs and human Wilms tumors expressed vimentin, SMA and β-catenin. The blastemal components of rat nephroblastomas and human Wilms tumors expressed vimentin, CD117/c-kit and β-catenin. The epithelial components of rat nephroblastomas and human Wilms tumors expressed vimentin and β-catenin. WT1 was expressed in different cellular components of rat tumors as compared with human Wilms tumors; the expression was seen in mesenchymal tumors and blastemal components of nephroblastomas in rats and epithelial components in human Wilms tumors. CK, p63 and CD57 were not expressed in rat RMTs or nephroblastomas, while CK and WT1 were expressed in epithelial components and CD57 was expressed in blastemal and epithelial components of human Wilms tumors. Rat and human tumors were universally negative for the expression of desmin and S-100. The immunohistochemical characteristics of rat renal tumors and human Wilms tumors may provide valuable information on the differences in renal oncogenesis and biology between the two species.

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Role of DNA repair in carcinogen-induced ras mutation

Engelbergs¹,

Thomale²,

Rajewsky³

2000

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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K-ras codon 12 and 61 point mutations in bromodeoxyuridine- and N-nitrosomethylurea-induced rat renal mesenchymal tumors

Cited by 5 publications

References 14 publications

Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis

Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis

<i>N</i>-Methyl-<i>N </i>-nitrosourea-induced Renal Tumors in Rats: Immunohistochemical Comparison to Human Wilms Tumors

Role of DNA repair in carcinogen-induced ras mutation

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