The importance of Topotecan in cancer

HER2 belongs to the Human Epidermal Growth Factor Receptor (HER) family of tyrosine kinases conisting of EGFR (HER1, erbB1), HER2 (erbB2, HER2/neu), HER3 (erbB3), and HER4 (erbB4). The importance of HER2 in cancer was realized in the early 1980s when a mutationaly activated form of its rodent homologue neu was identified in a search for oncogenes in a carcinogen induced rat tumorigenesis Topotecan model (Shih et al. 1981). Its human homologue HER2 was simultaneously cloned and found to be amplified in a GS-1101 breast cancer cell line (King et al. 1985). The relevance of HER2 to human cancer was established when it was discovered that approximately 25?C30% of breast cancers have amplification and overexpression of HER2 and these cancers have worse biologic behavior and prognosis (Slamon et al. 1989).
This finding established the HER2 oncogene hypothesis that overexpression of HER2 is etiologically linked with tumorigenesis in some human cancers. A substantial body of experimental evidence Adriamycin over the past two decades has come to solidly support this hypothesis. In numerous in vitro and transgenic models, HER2 overexpression by itself is potently transforming. In addition, analysis of human breast cancers has shown that amplification of the HER2 locus is an early event in human carcinogenesis and along with the experimental evidence confirming its potently transforming functions, this makes a highly compelling case implicating HER2 overexpression in the genesis of these human cancers.
The signaling functions of HER2, the body of evidence confirming the transforming functions of HER2, the numerous proposed mechanisms mediating its transforming functions, and the data establishing the relevance of these findings to human cancer pathogenesis were discussed in depth previously (Moasser 2007). A direct consequence of the HER2 oncogene hypothesis of human cancer was that inhibitors of oncogenic HER2 would be highly effective treatment for HER2 driven cancers. Here I will review where we stand with regards to testing this treatment hypothesis and where we currently stand with regards to the therapeutic implications of the HER2 oncogene hypothesis. The tumorigenic potential of HER2 is solidly supported by experimental models (Moasser 2007). This by itself proposes HER2 as a possible target for anti-cancer drugs.
However its suitability as a drug target is substantially strengthened by experiments demonstrating that HER2-driven tumors are dependent on LDE225 HER2 function. This dependency, recently labelled oncogene addiction, identifies oncogenes that are high value targets for drug development (Hynes and Lane 2001). Experimental models of HER2 overexpressing cancer cells using antisense, ribozyme, or siRNA methodologies consistently show that HER2 knockdown induces apoptosis in cell culture, or tumor regression in vivo, in the absence of HER2 expression, while tumor types that do not overexpress HER2 are not sensitive to HER2 knockdown (Colomer et al. 1994; Juhl et al. 1997; Roh et al. 2000; Faltus et al. 2004; Choudhury et al. 2004). Similar results are seen with kinase-dead HER2 and intracellular single chain anti-HER2 antibodies (Messerle et al. 1994; Beerli et al.
1994; Deshane et al. 1996). Engineered models of HER2-driven transformation using tetracycline inducible systems confirm that HER2 induced tumors require HER2 for continued tumorigenic growth and survival. This has been demonstrated in an HER2-transformed NIH3T3 tumor model wherein tumors regress upon withdrawal of the HER2 oncogene (Baasner et al. 1996; Schiffer et al. 2003). This has also been corroborated in a tet-inducible transgenic models. Tetracycline induced expression of activated HER2 in squamous epithelia of mice results in severe hyperplastic abnormalities of squamous epithelial tissues, which reverse upon withdrawal of the HER2 transgene expression (Xie et al. 1999). Tumors in MMTV-neuT mice are also dependent on continued oncogene expression. In the MMTV-rtTA/TetONeuNT bitransgenic variant of this model regulated by doxycycline, when expression of the neuT oncogene is PS-341 induced in the mammary tissue of adult mice, this leads to the formation of multiple mammary tumors and lung metastases, and the entire primary tumor and metastatic disease fully regresses when neuT expression is withdrawn (Moody et al. 2002).

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S1231 Topotecan HCl Topotecan HCl is a topoisomerase I inhibitor for MCF-7 Luc cells and DU-145 Luc cells with IC50 of 13 nM and 2 nM in cell-free assays, respectively. (7) (2)

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