New Understanding
of Etoposide After-Effect
June 2, 1998 Etoposide is a relatively new anticancer drug used for
prostate cancer among several other cancers. A new study shows that it appears
to work by cutting up the ends of chromosomes, a region known as the telomere.
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.
"WeÂve
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 UniversityÂs 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 didnÂt
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.
"ThatÂs 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 whatÂs actually happening in cells and on what the
downstream consequences are of telomere-specific damage."
Mark Muller is a professor of molecular genetics and a researcher with
Ohio State UniversityÂs Comprehensive Cancer Center. The study, co-authored
by Muller, was published in a recent issue of the journal Biochimica
et Biophysica Acta.
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
brand.
June 2, 1998. Modified December 26, '98
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