Podophyllotoxin cytotoxic agent

Podophyllotoxin is an aryltetralin lignan which has been isoiated from severai plants of the Podophyllum species, it is a potent cytotoxic agent against various cancer celi iines, stopping the cell cycle in metaphase through the inhibition of microtubules assembly by binding the colchicine site of the tubulin [112]. Because of numerous side effects, podophyllotoxin cannot be used as a drug. 

Podophyllotoxin and its derivatives are active cytotoxic agents with specific affinity for the microtubule protein of the mitotic spindle. Normal assembly of the spindle is prevented, and epidermal mitoses are arrested in metaphase. A 25% concentration of podophyllum resin in compound tincture of benzoin is recommended for the treatment of condyloma acuminatum. Application should be restricted to wart tissue only, to limit the total amount of medication used and to prevent severe erosive changes in adjacent tissue. In treating cases of large condylomas, it is advisable to limit application to sections of the affected area to minimize systemic absorption. The patient is instructed to wash off the preparation 2-3 hours after the initial application, since the irritant reaction is variable. Depending on the individual patient s reaction, this period can be extended to 6-8 hours on subsequent applications. If three to five applications have not resulted in significant resolution, other methods of treatment should be considered. 

The determination of the mechanism of action of Taxol proved to be very important in the clinical development of this cytotoxic agent. Initial studies demonstrated that it was a mitotic spindle inhibitor. However, subsequent studies demonstrated that the mechanism was unique because it stabilized microtubules and prevented their depolymerization back to tubulin, an effect opposite that of other antimitotic agents as colchicine, vincristine, vinblastine, and podophyllotoxin. ... 

The podophyllotoxin (Fig. 20.22) was isolated from the American mandrake Podophyllum pelatum), which had been traditionally used by American Indians as a laxative and anthelmintic, in 1880. It was subsequently shown to be a potent cytotoxic agent but was too toxic for use in cancer chemotherapy. Chemists at Sandoz in the 1950s further investigated Podophyllum species for analogues of podophyllotoxin. This eventually led to the development of the semi-synthetic compounds tenipinoside and etoposide (Fig. 21.22). These agents are topoisomerase II inhibitors. Teniposide is more cytotoxic than etoposide although it is not orally bioavailable. ... 

Podophyllotoxin (3.86) is used as an ectopic antiviral agent in the treatment of venereal warts. It is too cytotoxic to be ingested, but after chemical modifications podophyllotoxin can be used as a powerful anti-cancer... 

Gordaliza M, Garcia PA, del Corral JMM, Casho MA, Gomez-Zurita MA. Podophyllotoxin distribution, sources, apph-cation, and new cytotoxic derivatives. Toxicon 2004 44 441 59. Lee KH, Xiao Z. The podophyllotoxins and analogs. In Antitumor Agents from Natural Sources. Kingston DGI, Cragg GM, Newman DJ, eds. 2005. CRC Press, Boca Raton, IT-. 

Taxol (42) is highly cytotoxic and has broad antitumor activity. This alkaloid acts by a mechanism different than any other antitumor drug. At concentrations completely inhibitory to cell division, taxol had no significant effects on DNA, RNA, or protein synthesis, but HeLa cells were blocked in late G2 and/or M phase. In contrast to other antimitotic agents such as colchicine, maytansine, vincristine, or podophyllotoxin, taxol (42) was found to promote assembly of calf-brain microtubules, and the microtubules so produced were resistant to depolymerization by cold or CaCl2. 

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