Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours

Kitzen, Jos; Jonge, Maja J.A. de; Lamers, Cor H.J.; Eskens, Ferry A.L.M.; Biessen, D. van der; Doorn, Leni van; Steeg, Judith ter; Brandely, M.; Puozzo, Ch.; Verweij, Jaap

doi:10.1016/j.ejca.2009.01.026

Cited by 76 publications

(72 citation statements)

References 22 publications

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“…PG490-88 has been approved entry into Phase I clinical trials for prostate cancer, suggesting that this drug might be a promising candidate for antitumor activity against prostate cells [80]. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and promotes apoptosis of human tumor cells [81]. Kitzen J.J. et al performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumors.…”

Section: Novel Derivatives Of Triptolidementioning

confidence: 99%

Triptolide and its expanding multiple pharmacological functions

Liu

2011

International Immunopharmacology

294

197

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Section: Novel Derivatives Of Triptolidementioning

confidence: 99%

Triptolide and its expanding multiple pharmacological functions

Liu

2011

International Immunopharmacology

294

197

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“…Table 1 summarizes the preclinical pharmacological study of triptolide and PG490-88/F60008 against autoimmune diseases and transplantation rejection. Although PG490-88 or F60008 has been approved for entry into a Phase I clinical trial for the treatment of solid tumors, two lethal events were observed in twenty patients, and the high inter-individual variability rendered PG490-88 or F60008 a far from optimal derivate of triptolide [28,29] . Great efforts have been made at the SIMM in the search for promising triptolide analogs with a low toxicity and relative high immunosuppressive activity, and a series of novel triptolide analogs have been successfully synthesized.…”

Section: Twhf a Representative Chinese Medicinal Herb Showing Immunomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In 1993, the ethyl acetate (EA) extract of TwHF was entered into a Phase I study for the treatment of RA patients [21][22][23][24][25] , and many clinical trials have tested triptolide for the treatment of RA and psoriasis [26,27] . In addition, PG490-88/F60008 (Figure 1), a water-soluble prodrug of triptolide, has been approved for entry into a Phase I clinical trial for the treatment of solid tumors [28,29] .The Shanghai Institute of Materia Medica (SIMM) has made great efforts to discover drugs from natural products that are of clinical value and have contributed to the treatment of autoimmune diseases, such as RA, SLE, and multiple sclerosis (MS). By combining basic and applied research efforts and through the collaboration between chemistry and biology, the SIMM has developed several series of immunosuppressive drug candidates against autoimmune diseases: LLDT-8 ( Figure 1), a novel triptolide analog from the Chinese traditional herb TwHF, that will enter into a Phase II clinical trial involving RA patients in China [30][31][32][33][34][35][36][37][38][39][40] ; SM934, a water-soluble derivative of artemisinin; and periplocoside E, a pregnane glycoside identified from Periploca sepium Bge.…”

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Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8)

Tang

Zuo

2012

Acta Pharmacol Sin

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The Chinese traditional herb Tripterygium wilfordii Hook f (TwHF) has been widely used in the treatment of autoimmune and inflammatory diseases. Over the past few decades, great efforts have been made to explore modern preparations of TwHF with higher efficacy, solubility, and lower toxicity. In this study, we reviewed several examples both of naturally occurring compounds and their derivatives in TwHF, and summarized the preclinical evaluations with regard to autoimmune and inflammatory diseases. All of the candidate compounds described herein have been or are currently in clinical trials. Although some studies encountered problems, the data still provided valuable references for future studies. (5R)-5-hydroxytriptolide (LLDT-8, Leitengshu) is a novel triptolide derivative with potent immunosuppressive and anti-inflammatory activities developed at Shanghai Institute of Materia Medica. Indeed, a Phase I clinical trial for this compound has been completed in rheumatoid arthritis patients. The results will provide the basis for the further exploration of this ancient herb and encourage the research and development of valuable traditional Chinese medicine. IntroductionFor thousands of years, natural products have played an important role throughout the world in treating and preventing human diseases [1][2][3][4][5] . The discovery and development of immunosuppressants from natural sources have an impressive record: mycophenolic acid (MPA) and cyclosporin A (CsA), the fungal metabolites isolated in 1932 [6] and 1970 [7] , respectively; rapamycin, found in 1975 [8] ; FK506, extracted from a culture filtrate of Streptomyces tsukubaensis in 1987 [9,10] ; and fingolimod (FTY720), described in 1995 [11] . Although the current industry model for drug discovery does not favor natural products, the resources are so vast as to seem unlimited, and these emerging tools will provide important discoveries, leading to new medicines [12] . Furthermore, the drugs already in use as immunosuppressants (eg, cyclophosphamide, methotrexate, azathioprine, cyclosporin) are associated with some significant problems, including toxicity, a lack of reversibility, and increased susceptibility to viral and other infections [13] . Indeed, exploring new and innovative immunosuppres-* To whom correspondence should be addressed.E-mail jpzuo@mail.shcnc.ac.cn Received 2012-06-11 Accepted 2012-07-04 sants from natural sources has now become a focus of intense research.Tripterygium wilfordii Hook f (TwHF) and its extracts have been widely used in the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and dermatomyositis (DM) [14][15][16][17][18] , and have beneficial effects on tissue and organ transplantation [19,20] . In 1993, the ethyl acetate (EA) extract of TwHF was entered into a Phase I study for the treatment of RA patients [21][22][23][24][25] , and many clinical trials have tested triptolide for the treatment of RA and psoriasis [26,27] . In addition, PG490-88/F60008 (F...

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“…The most promising clinical candidate is a derivative of the diterpene triepoxide, triptolide, termed F60008. A phase I study with this compound in France was only partially successful due to the toxicity of the semisynthetic derivative (Kitzen et al, 2009). There is still considerable enthusiasm for minnelide (Arora et al, 2015), a prodrug derivative of triptolide, which is currently undergoing phase I clinical trials as a treatment for advanced gastrointestinal tumors in the United States (clinicaltrials.gov identifier NCT01927965).…”

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Integrative Approaches for the Identification and Localization of Specialized Metabolites in Tripterygium Roots

et al. 2016

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ORCID IDs: 0000-0001-6565-9584 (B.M.L.); 0000-0001-7934-7987 (N.S.); 0000-0002-0600-6847 (D.Š.).Members of the genus Tripterygium are known to contain an astonishing diversity of specialized metabolites. The lack of authentic standards has been an impediment to the rapid identification of such metabolites in extracts. We employed an approach that involves the searching of multiple, complementary chromatographic and spectroscopic data sets against the Spektraris database to speed up the metabolite identification process. Mass spectrometry-based imaging indicated a differential localization of triterpenoids to the periderm and sesquiterpene alkaloids to the cortex layer of Tripterygium roots. We further provide evidence that triterpenoids are accumulated to high levels in cells that contain suberized cell walls, which might indicate a mechanism for storage. To our knowledge, our data provide first insights into the cell type specificity of metabolite accumulation in Tripterygium and set the stage for furthering our understanding of the biological implications of specialized metabolites in this genus.

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Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours

Cited by 76 publications

References 22 publications

Triptolide and its expanding multiple pharmacological functions

Triptolide and its expanding multiple pharmacological functions

Immunosuppressant discovery from Tripterygium wilfordii Hook f: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8)

Integrative Approaches for the Identification and Localization of Specialized Metabolites in Tripterygium Roots

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