Tumor-Specific Novel Taxoid−Monoclonal Antibody Conjugates

Ojima, Iwao; Geng, Xu; Wu, X. Ben; Qu, Chuanxing; Borella, Christopher P.; Xie, Hongsheng; Wilhelm, Sharon; Leece, Barbara; Bartle, Laura M.; Goldmacher, Victor S.; Chari, Ravi

doi:10.1021/jm025540g

Cited by 115 publications

(127 citation statements)

References 19 publications

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“…31 However, the nondiscriminating side effects on normal tissue and the multi drug resistance limited the efficacy of Taxol. 14,32 The EC 50 of A431 cells to Taxol alone is about 90 pM, 32 our data showed that the IC 50 of the Fab-Taxol conjugate was about 20 pM (Fig. 6A), four-to five-fold more potent than Taxol when analyzed by the cell proliferation inhibition assay.…”

Section: Discussionmentioning

confidence: 68%

In vitro efficacy of immuno-chemotherapy with anti-EGFR human Fab-Taxol conjugate on A431 epidermoid carcinoma cells

Wang¹,

Zhu²,

Zhao³

et al. 2007

Cancer Biology & Therapy

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The aims of this study were to generate a human Fab fragment against EGFR; conjugate it to paclitaxel (Taxol) as an immuno-chemotherapy agent; and investigate its in vitro anti-tumor efficacy on A431 epidermoid carcinoma cells. A431 cells (EGFR-positive), NIH 3T3 cells (EGFR-negative), and purified EGFR were used for subtractive panning on a human naïve Fab phage library to generate a human anti-EGFR Fab fragment that binds the EGFR extracellular domain in native conformation and subsequently internalizes it into the cytosol. The Fab was then conjugated with the chemotherapeutic Taxol, and cell proliferation inhibition and apoptosis (TUNEL) assays were conducted to determine the effect of this Fab-drug conjugate on A431 cells. The specificity and internalization property of this Fab were characterized by immunoprecipitation, fluorescence staining, flow cytometry, and Hum-Zap assay. The binding affinity to purified EGFR was 30 nM. The Fab-Taxol conjugate inhibited A431 cell proliferation at low concentrations and in a dose-responsive manner; more than 70% inhibition was observed at 52 pM. Furthermore, almost 100% of cells underwent apoptosis after treatment with Fab-Taxol at 26 pM for 48 hours. Our findings suggest that this Fab-Taxol conjugate could be a potential immuno-chemotherapeutic drug for clinical treatment of EGFR-overexpressing tumors.

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Section: Discussionmentioning

confidence: 68%

In vitro efficacy of immuno-chemotherapy with anti-EGFR human Fab-Taxol conjugate on A431 epidermoid carcinoma cells

Wang¹,

Zhu²,

Zhao³

et al. 2007

Cancer Biology & Therapy

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“…Antibodies (their size is about 12 nm) endowed with fluorescent dyes (e.g., Alexa Fluor 488 λEm=525 nm and Texas Red λEm=609 nm) [15][16][17] were used in the development of a wide range of effective targeted therapies [18][19][20][21][22] but they create clustering artifacts due to limited antibody penetration, which have an impact on insufficient labeling density. Thus, ligands that have been exploited for chemotherapeutic agent targeting systems can include monoclonal antibodies [23][24][25][26][27][28] but also low molecular weight receptor-binding conjugates such as dyelabeled peptides (arginine-glycine-aspartic acid-Cyt5,5) [29], peptide hormones [30,31], receptor antagonist and agonists [32], aptamers [33][34][35], transferrin [36][37], oligosaccharides [38], glycoconiugates [39], polyunsaturated fatty acids [40], oligopeptides [41,42], vitamin B12 [43], folic acid [44][45][46][47][48][49][50][51][52][53][54] and hyaluronic acid [55,56]. These ligands can be regarded as a tumor-specific receptor to construct a "guided molecular ...…”

Section: Fluorescent Small Molecules As Cell-type-specific Imaging Prmentioning

confidence: 99%

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

Miksa¹

2016

Med chem (Los Angeles)

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This review highlights the role of fluorescent dyes as active "molecular photoswiches" focusing on the application in bioimaging and anticancer therapies in the field of therapeutic delivery. The author describes the development of prodrugs targeted to specific cell types and polymeric nanocarriers (capsules, micelles and silica nanoparticles) used as fluorescent probes which offer advantages in the integration of "smart" features of fluorescent dyes into synthetic materials. The incorporation of biologically responsive components that cleave upon changes in pH or light irradiation is fundamental to the successful design of such carriers with capabilities to load and release therapeutics specifically at a target site.

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“…It is also a stabiliser of microtubules and is cytotoxic against several human cells. It is used in the treatment of locally advanced metastatic breast cancer and non-small-cell lung cancer [152][153][154][155][156] (Fig. 9).…”

Section: Paclitaxel (Taxol ® ) and Docetaxel (Taxotere ® )mentioning

confidence: 99%

Natural products as leads to anticancer drugs

2007

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Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as "lead" compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

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Tumor-Specific Novel Taxoid−Monoclonal Antibody Conjugates

Cited by 115 publications

References 19 publications

In vitro efficacy of immuno-chemotherapy with anti-EGFR human Fab-Taxol conjugate on A431 epidermoid carcinoma cells

In vitro efficacy of immuno-chemotherapy with anti-EGFR human Fab-Taxol conjugate on A431 epidermoid carcinoma cells

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

Natural products as leads to anticancer drugs

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