4- Epipodophyllotoxin

Epipodophyllotoxins (etoposide, teniposide) are derived from mandrake root (Podophyllum peltatum). They inhibit topoisomerase H thus causing double strand breaks. Cells in S- and G2-phases are most sensitive. Unwanted effects include nausea and vomiting, myelosuppression, and hair loss. 

Hypersensitivity reactions have occurred with all cancer chemotherapeutic agents. Reactions are most common with the taxanes, platinum compounds, asparaginases, and epipodophyllotoxins.7 Reactions range from mild (e.g., flushing and rashes) to severe (e.g., dyspnea, bronchospasm, urticaria, and hypotension). IgE-mediated type I reactions are the most common. To reduce the risk, patients are routinely pre-medicated... 

For patients with myelodysplastic syndrome or AML as a secondary neoplasm, there are a number of key features characteristic of the leukemia. Alkylator-related secondary leukemias after Hodgkin s disease usually have a myelodysplastic prodrome and a monosomy 5 or monosomy 7. Secondary ANLL with the use of epipodophyllotoxin (etoposide) demonstrates mainly M4 or M5 morphology and exhibits translocations within the MLL gene with 1 lq23 chromosomal alterations.8... 

Hyaluronidase is the antidote of choice for vinca alkaloid and high-concentration epipodophyllotoxin extravasations. Hyaluronidase breaks down hyaluronic acid, which functions as tissue cement. This promotes absorption of the extravasated drug away from the local site. Hyaluronidase also may be used for paclitaxel extravasations, but there are conflicting reports regarding its efficacy.39 Hyaluronidase should not be used with anthracycline extravasations because enhancement of local spread may occur. 

Epipodophyllotoxin (122) Alkaloid Tafluposide (123) Oncology Topoisomerase I and II inhibitor Phase I Pierre Fabre 727-729... 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

The epipodophyllotoxins, etopo-side and teniposide, interact with topo-isomerase 11, which functions to split, transpose, and reseal DNA strands (p. 274) these agents cause strand breakage by inhibiting resealing. 

Augmented drug extrusion increased synthesis of the P-glycoprotein that extrudes drugs from the cell (e.g., anthracyclines, vinca alkaloids, epipodophyllotoxins, and paclitaxel) is re-ponsible for multi-drug resistance (mdr-1 gene amplification). 

Teniposide is used for the same indications as etoposide however, it is 5-10 times more potent than etoposide. Synonyms of this drug are epipodophyllotoxin, vumon, and others. 

Multiple-drug chemotherapy regimens consisting of various combinations of BCNU, hydroxyurea, procarbazine, and/or VM-26 (epipodophyllotoxin) showed no significant survival advantage over BCNU alone (BTCG 8001). 

Stewart DJ, Grahovac Z, Benoit B, et al. Intracarotid chemotherapy with a combination of l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), cis-diaminedichloroplatinum (cisplatin), and 4 -0-demethyl-l-0-(4,6-0-2-thenylidene-beta-D-glucopyranosyl)epipodophyllotoxin (VM-26) in the treatmentof primary and metastatic brain tumors. Neurosurgery 1984 15(6) 828-833. 

In principle there is no cross-resistance among the individual vinca alkaloids. However cells which are multidrug-resistant due to an activated efflux pump may display cross-resistance to vinca alkaloids, the epipodophyllotoxins, anthracyclines. 

Tafluposide (F 11782) is an epotoside (epipodophyllotoxin) derivative (cf. Chapter 4) where the two hydroxyls of the glycosidic moiety are acylated with pentafluorophenoxyacetic acid (Figure 8.7). It has been demonstrated that tafluposide does not act as a prodrug of epotoside, but it has a unique mechanism of interaction with both topoisomerases I and... 

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