Design, Synthesis, and Biological Evaluation of New-Generation Taxoids

Ojima, Iwao; Chen, Jin; Sun, Liang; Borella, Christopher P.; Wang, Tao; Miller, Michael L.; Lin, Songnian; Geng, Xu; Kuznetsova, Larisa; Qu, Chuanxing; Gallager, David; Zhao, Xianrui; Zanardi, Ilaria; Xia, Shujun; Horwitz, Susan Band; Clair, Jon Mallen–St.; Guerriero, Jennifer L.; Bar–Sagi, Dafna; Veith, Jean; Pera, Paula; Bernacki, Ralph J.

doi:10.1021/jm800086e

Cited by 92 publications

(159 citation statements)

References 56 publications

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“…Second-generation taxanes SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 [20,37], SB-T-1214 [16,36], IDN5109 [20,21], and IDN5390 [22] were synthesized by the Ojima laboratory, State University of New York at Stony Brook, U. S. A. Their structures are shown in Fig.…”

Section: Drugsmentioning

confidence: 99%

Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes

et al. 2011

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The study investigated possible mechanisms by which second-generation taxanes, established as significantly more effective than paclitaxel in vitro, suppress a rat lymphoma model in vivo. The studied mechanisms included taxane pharmacokinetics, expression of genes dominating their metabolism (Cyp3a1/2) and transport (Abcb1) and genes controlling tumour angiogenesis (growth factors and receptors). SB-T-1214, SB-T-12854 and IDN5109 suppressed rat lymphoma more effectively than paclitaxel, SB-T-12851, SB-T-12852, SB-T-12853 or IDN5390 as well as P388D1 leukaemia cells in vitro. The greater anti-lymphoma effects of SB-T-1214 in rats corresponded to a higher bioavailability than with SB-T-12854, and lower systemic toxicity of SB-T-1214 for rats reflected its lower cytotoxicity for P388D1 cells in vitro. Suppression of Abcb1 and CYP3a1 expression by SB-T-1214 and IDN5109 could partly explain their anti-lymphoma effects, but not that of SB-T-12854. Growth factors genes Egf, Fgf, Pdgf, and Vegf associated with tumour angiogenesis had significantly lower expression following treatment with anti-lymphoma effective IDN5109 and their receptors were unaffected, whereas inefficient IDN5390 increased expression of the most important Vegf. The effective SB-T-12854 inhibited Egf, Egfr, Fgfr and Pdgfr expression, while the ineffective SB-T-12851, SB-T-12852 and SB-T-12853 inhibited only Egf or Egfr expression. Vegfr expression was inhibited significantly by SB-T-12851 and SB-T-12854, but effect of SB-T-12851 was compromised by induced Vegf expression. The very effective SB-T-1214 decreased the expression of Vegf, Egf and all receptors most prominently indicating the possible supporting role of these genes in anti-lymphoma effects. In conclusion, SB-T-1214, SB-T-12854 and IDN5109 are good candidates for further study.

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Section: Drugsmentioning

confidence: 99%

Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes

et al. 2011

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“…SB-T-1214, one of the new-generation taxoids which was developed as an attempt to improve widely used taxane-based anticancer agents [62], has been demonstrated to induce growth inhibition and apoptotic cell death in drug resistant [63,64] and tumorigenic CD133+/CD44+ colon cancer spheroids [65], suggesting that this compound can specifically target tumor-specific SCLCs by inhibiting some stemness-related signaling pathways.…”

Section: Influence Of Sclcs In the Therapeutic Settingmentioning

confidence: 99%

Cancer Cells with Stem Cell-Like Phenotypes and Liver Metastasis from Colon Carcinoma

Bellizzi¹,

Tommasi²

2013

J Liver

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Tumor heterogeneity contributes to the potentiality of tumors to invade and metastasize. Thus the identification of specific cells programmed to go to a specific site and establish themselves, actively proliferating and causing metastasis, could be fundamental for early diagnosis and for selective targeted therapy. Apart from gene signatures which seem to identify this tumor ability, selected cell populations with self-renewal potential have been recognized: stem cell-like cancer cells. In this paper we review recent evidence on the identification of colon cancer cells with stem cell-like properties which could have a key role in the liver metastasization. The potential clinical implication of their therapeutic eradication is also discussed. Keywords: Stem Cell-Like Cancer cells (SCLC); Colon cancer; MetastasisColorectal Cancer (CRC) is the third most common cancer in men (663,000 cases, 10.0% of the total) and the second in women (570,000 cases, 9.4% of the total) worldwide. Almost 60% of the cases occur in developed regions [1] and approximately 50% of patients develop synchronous or metachronous liver metastases within 2 years from the resection of the primary tumor [2]. Most colon cancer deaths result from the metastatic spread of tumor cells to the liver and other organs [3] and for this reason it is of great significance to identify new markers capable of discriminating earlier the potential that a primary tumor has to initiate a process of liver metastasization. The standard care in patients with operable liver-confined lesions is represented by a combination of chemotherapy and surgery [4]. However, there are still some critical issues to be solved. Firstly, surgical cures are relatively rare in this setting. Secondly, how to juxtapose chemotherapy and surgery, and the duration of chemotherapy. Finally, the possibility of pre-operative chemotherapy in the case of resectable metastases [5]. This is primarily due to the fact that current chemotherapy attacks the bulk of the cancer without affecting the chemo-resistant Stem Cell-Like Cancer cells (SCLCs). These can re-grow after treatment and, eventually, develop the changes responsible for the occurrence of drug-resistance [6][7][8] and facilitate a persistent and aggressive tumor phenotype, capable of invading other sites. In this scenario, understanding what drives metastasization to the liver and the characterization of clonal cells which selectively establish themselves in that site acquires great importance.In CRC, SCLCs are colon stem cells progenitors whose deregulated dynamics lead to the origin of a tumor [9]. At least two populations of progenitors are identified at the bottom of the normal colon Lieberkühn: true quiescent stem cells with high chemoresistance, and low proliferating potential [10]. They produce continuously the second compartment of stem cell progenitors with high mitogenic, differentiation and migratory potentials towards the top epithelium surface of the crypts. Upon migration upward through the crypt, these cells proli...

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“…The taxanes, including paclitaxel and docetaxel, have poor BBB permeability that is thought to result, at least in part, from these molecules being substrates for the P-glycoprotein (Pgp) transporter that prevents xenobiotics from accumulating in the brain (Sparreboom et al 1997;Fellner et al 2002). Improved taxanes have been synthesized that are not Pgp substrates (Cisternino et al 2003;Ballatore et al 2007a;Ojima et al 2008;Metzger-Filho et al 2009), but recent data from our laboratory suggest that such compounds still have poor brain penetration (Brunden et al 2011). However, several examples from the epothilone class of MT-stabilizing compounds, some of which have progressed to clinical testing for cancer (Altmann 2005;Beer et al 2007; Denduluri al.…”

Section: Compensation For Tau Loss-of-functionmentioning

confidence: 99%

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

Lee¹,

Brunden²,

Hutton³

et al. 2011

Cold Spring Harbor Perspectives in Medicine

107

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Design, Synthesis, and Biological Evaluation of New-Generation Taxoids

Cited by 92 publications

References 56 publications

Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes

Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes

Cancer Cells with Stem Cell-Like Phenotypes and Liver Metastasis from Colon Carcinoma

Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets

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