Etoposide phosphate, the water soluble prodrug of etoposide

Witterland, A. H. I.; Koks, C. H. W.; Beijnen, Jos H.

doi:10.1007/bf00820727

Cited by 34 publications

(18 citation statements)

References 32 publications

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“…It is also used to treat lymphomas and nonlymphocytic leukemia. To improve its water solubility, a prodrug etoposide phosphate (Etophos) was developed for intravenous use [298,299]. Teniposide is an analog of etoposide and is approved for the treatment of acute lymphoblastic leukemia (ALL) in children [300].…”

Section: Htop 2-targetting Anticancer Drugsmentioning

confidence: 99%

Topoisomerases as anticancer targets

Delgado

Hsieh

Chan

et al. 2018

Biochemical Journal

369

226

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Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or non-specific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proven therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase-drug-DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting a certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.

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Section: Htop 2-targetting Anticancer Drugsmentioning

confidence: 99%

Topoisomerases as anticancer targets

Delgado

Hsieh

Chan

et al. 2018

Biochemical Journal

369

226

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“…For the same purpose, it has also been administered together with androgens to decrease toxicity in the treatment of prostate cancer [109]. More recently, etopophos, a prodrug of etoposide, has been approved for clinical use [95,110].…”

Section: Podophyllotoxin Etoposide and Teniposidementioning

confidence: 99%

Antitumor Properties of Podophyllotoxin and Related Compounds

Gordaliza¹,

Ma²,

Jm³

et al. 2000

CPD

255

143

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The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.

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“…Aiming to find novel PPT derivatives with high efficiency and low toxicity, researchers carried out a series of structural modifications with podophyllin ingredients and obtained three potent semisynthetic glucoconjugates based on 4′-demethylpodophyllotoxin (DPPT, 2 ), including etoposide ( 3 ), teniposide ( 4 ), and a water-soluble prodrug of etoposide, named etopophos (etoposide phosphate, 5 ) (Figure 1) (Keller-Juslen et al, 1971; Greco and Hainsworth, 1996; Damayanthi and Lown, 1998; Hande, 1998). The semisynthetic glucoconjugates displayed favorable water solubility and are currently in clinical use for the treatment of various malignancies, including small cell lung cancer, testicular carcinoma, lymphoma, non-lymphocytic leukemia, and multiform glioblastoma (Issell, 1982; Loike, 1982; Witterland et al, 1996; Liu et al, 2015; Moon et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 4β-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents

Wei

Chen

et al. 2019

Front. Chem.

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A series of novel podophyllotoxin derivatives obtained by 4β-N-acetylamino substitution at C-4 position was designed, synthesized, and evaluated for in vitro cytotoxicity against four human cancer cell lines (EC-9706, HeLA, T-24 and H460) and a normal human epidermal cell line (HaCaT). The cytotoxicity test indicated that most of the derivatives displayed potent anticancer activities. In particular, compound 12h showed high activity with IC 50 values ranging from 1.2 to 22.8 μM, with much better cytotoxic activity than the control drug etoposide (IC 50 : 8.4 to 78.2 μM). Compound 12j exhibited a promising cytotoxicity and selectivity profile against T24 and HaCaT cell lines with IC 50 values of 2.7 and 49.1 μM, respectively. Compound 12g displayed potent cytotoxicity against HeLA and T24 cells with low activity against HaCaT cells. According to the results of fluorescence-activated cell sorting (FACS) analysis, 12g induced cell cycle arrest in the G2/M phase accompanied by apoptosis in T24 and HeLA cells. Furthermore, the docking studies showed possible interactions between human DNA topoisomerase IIα and 12g. These results suggest that 12g merits further optimization and development as a new podophyllotoxin-derived lead compound.

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Etoposide phosphate, the water soluble prodrug of etoposide

Cited by 34 publications

References 32 publications

Topoisomerases as anticancer targets

Topoisomerases as anticancer targets

Antitumor Properties of Podophyllotoxin and Related Compounds

Synthesis and Biological Evaluation of 4β-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents

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