Transcriptional Effects of the Potent Enediyne Anti-Cancer Agent Calicheamicin γ1I

Watanabe, Coran M. H.; Supeková, Lubica; Schultz, Peter G.

doi:10.1016/s1074-5521(02)00103-5

Cited by 22 publications

(15 citation statements)

References 47 publications

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“…66 Microarray studies of yeast cells indicate that calicheamicin-g 1 induces changes in transcript levels of genes involved in DNA repair and synthesis, chromatin rearrangement, cell cycle checkpoint control, nuclear proteins, ribosomal proteins, metabolic and biosynthetic genes, and proteins involved in stress response. 67 Similar analyses have not yet been reported for GO-induced cytotoxicity in human cells.…”

Section: Go-induced Cytotoxicitymentioning

confidence: 55%

CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance

2004

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CD33 is expressed on the malignant blast cells in most cases of acute myeloid leukemia (AML) but not on normal hematopoietic pluripotent stem cells. Antibody-based therapies for AML have, therefore, focused on CD33 as a suitable tumor-associated target antigen. The most promising results have been obtained with gemtuzumab ozogamicin (GO, Mylotargt), a humanized IgG 4 anti-CD33 monoclonal antibody joined to a calicheamicinc 1 derivative. Engagement of CD33 by GO results in immunoconjugate internalization and hydrolytic release of the toxic calicheamicin moiety, which, in turn, causes DNA damage and cell death. Since 2000, when GO was approved for clinical use, treatment trials and pilot studies have revealed potential expanded applications along with additional limitations. At the same time, correlative biological and in vitro functional studies have further characterized CD33 expression patterns in AML, the significance of CD33-antibody interactions, pathways involved in GO-induced cytotoxicity and potential drug resistance mechanisms. This review summarizes the recent data addressing mechanisms of GO action and discusses their relevance with regard to clinical applications and the limitations of using experimental model systems to mimic in vivo conditions. As the first drug conjugate approved for clinical use, GO serves as an important paradigm for other immunoconjugates against internalizing tumor antigens.

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Section: Go-induced Cytotoxicitymentioning

confidence: 55%

CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance

2004

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“…In general, these enediynes contain three distinct structural elements: a DNArecognition unit, which serves to deliver the metabolite to its target DNA; an activation component, which sets the stage for cycloaromatization; and the enediyne ''warhead,'' which cycloaromatizes to a highly reactive diradical species and, in the presence of DNA, results in oxidative strand scission of the targeted sequence (7)(8)(9)(10). In vitro and in vivo studies are consistent with the role of enediynes as DNA-damaging agents and suggest that they may even favor cleavage at certain chromosomal sites and͞or tertiary structures (11,12). Although this extraordinary reactivity invokes incredible potency (some enediynes are Ͼ8,000-fold more potent than adriamycin), the enediynes are similar to most cytotoxics in their general lack of tissue specificity.…”

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confidence: 77%

Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model

Ahlert

Gao

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

129

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A universal PCR method for the rapid amplification of minimal enediyne polyketide synthase (PKS) genes and the application of this methodology to clone remaining prototypical genes from producers of structurally determined enediynes in both family types are presented. A phylogenetic analysis of the new pool of bona fide enediyne PKS genes, consisting of three from 9-membered producers (neocarzinostatin, C1027, and maduropeptin) and three from 10-membered producers (calicheamicin, dynemicin, and esperamicin), reveals a clear genotypic distinction between the two structural families from which to form a predictive model. The results from this study support the postulation that the minimal enediyne PKS helps define the structural divergence of the enediyne core and provides the key tools for generating enediyne hybrid genes͞molecular scaffolds; by using the model, a classification is also provided for the unknown enediyne PKS genes previously identified via genome scanning.

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“…Calicheamicin (Fig. 4), possibly the most potent antitumor compound to be approved for clinical use, languished for a number of years as it was just too toxic to pursue, in spite of its exquisite subpicomolar level activity [29,30]. The compound has been linked to a specific monoclonal antibody directed against chronic myologenous leukemia, and recently has been approved for clinical use as Mylotarg ® .…”

Section: Microbial Sources and The Golden Age Of Antibioticsmentioning

confidence: 99%

Biodiversity: A continuing source of novel drug leads

Cragg

Newman

2005

Pure and Applied Chemistry

324

219

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Nature has been a source of medicinal agents for thousands of years and continues to be an abundant source of novel chemotypes and pharmacophores. With only 5 to 15 % of the approximately 250 000 species of higher plants systematically investigated, and the potential of the marine environment barely tapped, these areas will remain a rich source of novel bioactive compounds. Less than 1 % of bacterial and 5 % of fungal species are currently known, and the potential of novel microbial sources, particularly those found in extreme environments, seems unbounded. To these natural sources can be added the potential to investigate the rational design of novel structure types within certain classes of microbial metabolites through genetic engineering. It is apparent that Nature can provide the novel chemical scaffolds for elaboration by combinatorial approaches (chemical and biochemical), thus leading to agents that have been optimized on the basis of their pharmacological activities. The proven natural product drug discovery track record, coupled with the continuing threat to biodiversity through the destruction of terrestrial and marine ecosystems and the current low number of new chemical entities in pharmaceutical industry pipelines, provides a compelling argument in favor of expanded multidisciplinary and international collaboration in the exploration of Nature as a source of novel leads for the development of drugs and other valuable bioactive agents. BIODIVERSITY: MEDICINALS FOR THE MILLENNIA Recorded historyThroughout the ages, humans have relied on Nature for their basic needs for the production of foodstuffs, shelters, clothing, means of transportation, fertilizers, flavors and fragrances, and, not least, medicines. Plants have formed the basis of sophisticated traditional medicine systems that have been in existence for thousands of years. The first records, written on clay tablets in cuneiform, are from Mesopotamia and date from about 2600 B.C.; among the substances they used were oils of Cedrus species (cedar) and Cupressus sempervirens (cypress), Glycyrrhiza glabra (licorice), Commiphora species (myrrh), and Papaver somniferum (poppy juice), all of which are still in use today for the treatment of ailments ranging from coughs and colds to parasitic infections and inflammation. Egyptian medicine dates from about 2900 B.C., but the best known Egyptian pharmaceutical record is the Ebers Papyrus dating from 1500 B.C.; this documents some 700 drugs (mostly plants), and includes formulas, such as gargles, snuffs, poultices, infusions, pills, and ointments, with beer, milk, wine, and honey being commonly used as vehicles. The Chinese Materia Medica has been extensively documented over

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Transcriptional Effects of the Potent Enediyne Anti-Cancer Agent Calicheamicin γ1I

Cited by 22 publications

References 47 publications

CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance

CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance

Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model

Biodiversity: A continuing source of novel drug leads

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