Recent Developments in the Maytansinoid Antitumor Agents

Cassady, John M.; Chan, Kenneth K.; Floss, Heinz G.; Leistner, Eckhard

doi:10.1248/cpb.52.1

Cited by 323 publications

(214 citation statements)

References 148 publications

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“…It is 25-to 270-fold more potent than paclitaxel and 180-to 4,000-fold more potent than doxorubicin (5,6). However, its side effects and lack of specificity prevented it from clinical use (7).…”

Section: Introductionmentioning

confidence: 99%

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

Yan

Endo

Shen

et al. 2016

Molecular Cancer Therapeutics

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Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFa in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFa enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. Mol Cancer Ther; 15(3); 480-90. Ó2015 AACR.

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Section: Introductionmentioning

confidence: 99%

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

Yan

Endo

Shen

et al. 2016

Molecular Cancer Therapeutics

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“…The ansamitocins (Higashide et al, 1977), produced by the actinomycete, Actinosynnema pretiosum, belong to the family of the maytansinoids first isolated from higher plants ( Kupchan et al, 1972). They are notable for their extremely potent antitumor activity which is due to binding to the tubulin β-subunit, blocking the assembly of functional microtubules (Cassady et al, 2004). Both the rifamycins and ansamitocins are assembled by a type I polyketide synthase, using an aromatic starter unit, 3-amino-5-hydroxybenzoic acid (AHBA) which is biosynthesized by a branch of the shikimate pathway.…”

mentioning

confidence: 99%

“…The genes/enzymes responsible for each of these steps, and the order in which these reactions occur, were determined by individual inactivation experiments Spiteller et al, 2003). For practical reasons, we were particularly interested in the attachment of the ester side chain, catalyzed by Asm19.Despite its high antitumor activity in vivo and in animal models, maytansine failed in phase II clinical trials against a wide range of human cancers (Cassady et al 2004). This may well be …”

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confidence: 99%

Combinatorial biosynthesis—Potential and problems

Floss

2006

Journal of Biotechnology

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139

114

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Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author's laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations. KeywordsCombinatorial biosynthesis; metabolic engineering; natural products; rifamycin; maytansinoids; polyketides Combinatorial biosynthesis can be defined as the application of genetic engineering to modify biosynthetic pathways to natural products in order to produce new and altered structures using nature's biosynthetic machinery. The feasibility of this approach was first demonstrated in work by David Hopwood and colleagues (Hopwood et al., 1985). Following the cloning of the biosynthetic genes for the antibiotic actinorhodin from Streptomyces coelicolor (Malpartida & Hopwood, 1984), Hopwood and coworkers cloned some or all of these genes into the producers of the antibiotics medermycin (Takano et al., 1976) and dihydrogranaticin (Corbaz et al., 1957), respectively. The transformant of the medermycin producer, Streptomyces sp. AM-7161 produced, in addition to medermycin, large amounts of a new compound, mederrhodin A, which carried an additional hydroxy group characteristic of actinorhodin ( Figure 1). The transformant of the dihydrogranaticin producer, Streptomyces violaceoruber Tü 22 produced a new compound, dihydrogranatirhodin, which has the actinorhodin configuration at one and the dihydrogranaticin configuration at the other stereocenter of the isochromane quinone system. This work represents the first, albeit modest, implementation of the concept of combinatorial biosynthesis of natural products. Since then, a large number of examples encompassing a wide range of natural product classes have appeared in the literature, and this approach has been accepted as a useful tool to increase the chemical diversity of natural products (Staunton and Wilkinson, 2001;Walsh, 2002;Rix et al., 2002;Reeves, 2003). Following the author's primary interests, this article focuses on the application of the combinatorial biosynthesis approach to microbial natural products and within these to Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript ...

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“…The plants may contain a biologically inactive bacterially produced precursor, which is only converted into the potent final product in response to a signal resulting from the attack. Alternatively, and more plausibly, the bacterial production of the maytansinoid precursor could be triggered by a plant signal in response to the pathogen aggression (Cassady et al 2004).…”

Section: A Physical Interaction Merely? the Plausibility Of Horizontamentioning

confidence: 99%

“…producer organism. This alternative approach has the advantage of all the regulatory elements and resistance mechanisms required for ansamytocin formation being present and functional (Cassady et al 2004).…”

Section: Maytansinoids From Bacterial Endophytesmentioning

confidence: 99%

Endophytes: exploiting biodiversity for the improvement of natural product-based drug discovery

Staniek

Woerdenbag

Kayser

2008

Journal of Plant Interactions

130

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Endophytes, microorganisms that colonize internal tissues of all plant species, create a huge biodiversity with yet unknown novel natural products, presumed to push forward the frontiers of drug discovery. Next to the clinically acknowledged antineoplastic agent, paclitaxel, endophyte research has yielded potential drug lead compounds with antibacterial, antiviral, antioxidant, insulin mimetic, anti-neurodegenerative and immunosuppressant properties. Furthermore, while being implicated in livestock neurotoxicosis, some endophyte-produced alkaloids have been shown to display insecticidal activity. The endophyte-host relationship is postulated to be a 'balanced antagonism'. Moreover, the plausibility of horizontal gene transfer (HGT) hypothesis is taken into account. Knowledge of the genetic background of endophytic natural product biosynthesis is discussed on the basis of loline alkaloids, ergopeptines, lolitrems and maytansinoids. The current dynamic progress in genomics will contribute to a better understanding of endophytic microbes and to further exploiting them as a source of pharmaceutically relevant compounds.

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Recent Developments in the Maytansinoid Antitumor Agents

Cited by 323 publications

References 148 publications

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

Combinatorial biosynthesis—Potential and problems

Endophytes: exploiting biodiversity for the improvement of natural product-based drug discovery

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