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The finding may help explain a serious after-effect of the drug — in a small number of patients, it gives rise to often-fatal, secondary cancers.
Etoposide (also known as Vepesid or VP-16) is used in the treatment of leukemia and solid tumors including prostate cancer. In about 5 percent of patients, etoposide causes chromosomal defects that can lead to secondary leukemias. These leukemias often arise within a year or two of treatment, and they are usually fatal.
"We’ve unmasked a different kind of effect that etoposide has on cells, and this effect is important to study because this is a clinically useful drug with a rather serious complication," said Mark Muller, professor of molecular genetics and a researcher with Ohio State University’s Comprehensive Cancer Center. "These results help us understand where the drug acts inside the cell, and they may help us understand why it causes secondary cancers in some patients."
How This Drug Works
Etoposide is a member of a small class of drugs known as topoisomerase-II inhibitors. These drugs work by blocking the action of an enzyme found in cells known as topoisomerase II (topo II). The job of topo II is to untangle DNA strands during cell division; failure to do so is lethal to the cell. Topo II does this by making temporary breaks in DNA to allow another DNA strand to pass through it.
Normally, the enzyme then instantly re-joins the cut ends to repair the break. Etoposide prevents the enzyme from completing its repair step. "The drug actually subverts the enzyme into a DNA damaging agent," said Muller.
The researchers studied etoposide and five other topo II inhibitors on fragments of DNA that contained telomeres. Based on a knowledge of how the drugs interact with DNA, the researchers predicted that most topo-II inhibitors should cause breaks in telomeres. To test their prediction, they constructed fragments of DNA that ended with telomeres of different lengths. They then incubated the fragments with one topo-II inhibiting drug after another. Initially, the results were negative. "We got discouraged when we found that topo II didn’t act on telomeres," said Muller. Eventually, they tested etoposide. "It was positive beyond all belief. It knocked our socks off; we thought it was a mistake." Next, they looked for the effect in cancer cells grown in the laboratory. Again, etoposide damaged the telomeres.
"That’s what puts this experiment on the map," he said. "These results are significant because the telomere cutting also happened in the nucleus of living cells." Muller suspects that there is a link between the etoposide-related damage to telomeres and the secondary cancers that have been linked to the drug. "This damage may lead to a rearrangement of genetic information that unmasks oncogenes or other secondary mutations that cause the cells to become cancerous," he said. "This is still theoretical — a guilt-by-association phenomenon. We need more data on what’s actually happening in cells and on what the downstream consequences are of telomere-specific damage."
Studies reporting positive results with etopiside for prostate cancer include:
Semin Oncol 1997 Oct;24(5 Suppl 15):S15-S72S1577 Paclitaxel, estramustine, and etoposide in the treatment of hormone-refractory prostate cancer. Pienta KJ, Smith DC
Urology 1997 Nov;50(5):754-758 Oral estramustine and oral etoposide for hormone-refractory prostate cancer. Dimopoulos MA, Panopoulos C, Bamia C, Deliveliotis C, Alivizatos G, Pantazopoulos D, Constantinidis C, Kostakopoulos A, Kastriotis I, Zervas A, Aravantinos G, Dimopoulos C Department of Clinical Therapeutics, University of Athens School of Medicine, Greece.
Am J Clin Oncol 1997 Aug;20(4):383-386 Phase II study of estramustine, oral etoposide, and vinorelbine in hormone-refractory prostate cancer. Colleoni M, Graiff C, Vicario G, Nelli P, Sgarbossa G, Pancheri F, Manente P Division of Medical Oncology, City Hospital, Castelfranco Veneto, Italy.
J Clin Oncol 1998 May;16(5):1835-1843 Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer. Smith DC, Dunn RL, Strawderman MS, Pienta KJ
Etoposide, sold as VePesid, is also known as VP-16. It is a semisynthetic
derivative of a toxin (podophyllotoxin derived from a woodland plant,
the mayapple. Etoposide is one of the most widely used generic anti-cancer
drugs. It acts by inhibiting the protein synthesis and DNA replication
of tumor cells.
Immunex Corporation received FDA
clearance for etoposide injection (also known as VP-16), a generic
cancer chemotherapy agent indicated for the treatment of refractory testicular
tumors and small cell lung cancer, in March 1996.
For a brief chemical outline of Etoposide visit Pharmacology of Podophyllotoxin and Related Compounds at Indiana University site. For how this drug was derived from Podophyllum peltatum go to their page on the mayapple.
Worldwide sales of Etoposide are $500 million plus per annum.
IGT Pharma is developing "a commercially important
alternative route" in an effort to replace Etoposide with a proprietrary