With hundreds of potential cancer drugs seeking to prove their mettle, two old
drugs have been given new life by the discovery that they, too, have potent anti-
tumor effects.
One is thalidomide, the sedative that caused thousands of babies to be born
with severely malformed limbs in the late 1950s and early '60s. Years after
thalidomide was banned and discredited, Dr. Judah Folkman's laboratory discovered
that the drug was effective against tumors in mice _ properties Folkman attributed to
its ability to block new blood vessel formation.
Thalidomide does seem effective against some cancers, shrinking or arresting
malignancies in small trials of patients with brain and prostate cancer, AIDS-related
Kaposi's sarcoma and some other solid tumors.
Thalidomide recently made news after University of Arkansas researchers
reported that nearly a third of 84 patients with multiple myeloma, a cancer of the
bone marrow that is notoriously difficult to treat, responded favorably to the drug.
Of the 27 patients whose condition improved, eight were completely or almost
completely cured.
``So it does work in that disease,'' says Dr. Walter Stadler of the University
of Chicago.
But no one knows how. Robert D'Amato, a researcher in Folkman's lab at
Boston's Children's Hospital, originally hypothesized that thalidomide caused
truncated limbs in fetuses because it blocked the growth of blood vessels needed to
extend the limbs.
That's still a possibility, but other researchers have since theorized that
thalidomide may also shrink tumors by blocking a substance made by the body's immune
cells.
Because the U.S. government long has insisted on proof of safety as well as
efficacy before approving a new medication, thalidomide was not in use in this
country 40 years ago, when pregnant women in Europe, Canada and elsewhere were taking
the drug for morning sickness, with disastrous consequences.
In 1998, however, the Food and Drug Administration approved it for treatment
of a complication of leprosy. That means the drug is now available, and American
doctors can prescribe it for other uses too. Celgene Corp., which manufactures the
drug under the trade name Thalomid, has set up a program to make sure physicians
don't prescribe it for pregnant women, but otherwise there are no restrictions.
Stadler cautions the drug can cause short-term side effects including nerve
damage, drowsiness and confusion. And no one knows if it's safe to use for long
periods. But that's not likely to stop people who are dying of cancer and are out of
options.
That's the situation in which Natalia Mlynarczyk found herself last summer.
The 67-year-old Northwest Side woman had been diagnosed in the spring of 1998 with
Merkel cell carcinoma, a rare skin cancer that is fatal once it has spread.
Chemotherapy had been useless, and radiation had merely slowed the disease
momentarily.
Her doctors had sent her home to die. But then her family heard about a
neighborhood physician helping people with cancer.
In August, Dr. Maciej Drazkiewicz agreed to prescribe thalidomide, noting,
``She had nothing to lose.''
After about a month, Mlynarczyk says, the tumors that covered her face and
head became softer. Within six weeks, she says, ``no more tumors.''
That was in October. Drazkiewicz says she has been in complete remission
since.
Mlynarczyk has regained much of her strength and now is able to get around
with a cane or walker. She believes the drug has also helped the crippling arthritis
she has had for more than 20 years.
Another drug showing impressive results is interferon-alpha, which captured
national attention 20 years ago when some hyped it as a potential magic bullet for
cancer.
It fell far short of that expectation, but doctors now believe it can help
fight some cancers by cutting off their blood supply.
Indeed, the first-ever anti-angiogenic treatment in a human involved
interferon, whose properties were also being investigated in Folkman's lab.
``It was 1988,'' recalls Folkman, ``and Carl White, a cardiologist in Denver,
called me about a child with a hemangioma in the lung.''
Hemangiomas are congenital tumors of the blood vessels; although benign, they
are often fatal.
Folkman suggested White try interferon-alpha, because it was an approved drug
and animal experiments had shown it was a weak angiogenesis inhibitor.
Dr. White tried it, at a low dose, once a day. ``The disease went away,''
Folkman says.
Folkman and others now routinely treat life-threatening hemangiomas in infants
with interferon. ``Since 1990,'' he says, ``mortality among the patients we've
treated has dropped to about 9 or 10 percent from 40 to 50 percent.''
Folkman is convinced the drug works because it cuts off the tumor's blood
supply. Others aren't sure.
There's evidence interferon acts directly on malignant cells. ``We believe it
puts cells to sleep and makes them unable to divide,'' says Dr. Nicholas Vogelzang,
director of the Cancer Research Center at the University of Chicago.
He notes that while interferon has long been used to treat some rare cancers,
it is also effective in hepatitis and other viral diseases, and has recently shown
promise in multiple sclerosis. But, he adds, ``How and why it works . . . is
unknown.''
In the laboratory, interferon has also demonstrated that it can inhibit the
growth of new blood vessels that tumors need if they are to thrive. It is this
property that is making the drug attractive to some researchers now.
``Interferon was touted to be a wonder drug in the early 1980s,'' says Robert
Kerbel, an experimental oncology professor at the University of Toronto, ``and it
essentially bombed.''
Now, he says, it is administered in a way that maximizes its anti-angiogenic
effect: Instead of hitting patients with the highest dose they can tolerate,
researchers are trying it in much lower doses, more frequently and over longer
periods.
Dr. James Pluda, who oversees angiogenesis research at the National Cancer
Institute, says the agency will sponsor a large, randomized trial to see whether the
combination of interferon and thalidomide is effective in treating kidney cancer.
Among the putative anti-angiogenic agents being tested by the NCI are
compounds derived from sharks _ as are numerous over-the-counter products consumed in
the belief that they may prevent or cure cancer.
There is no scientific evidence that commercial shark-cartilage products offer
protection against cancer, and some evidence that they don't. Nor is it true, as some
believe, that sharks don't get cancer.
One agent under scrutiny is Neovastat, a liquid shark-cartilage extract made
by AEterna Laboratories, which stresses it is different from over-the-counter
supplements. A preliminary Canadian study suggested Neovastat helped patients with
advanced lung cancer to live half-again as long as similar patients not treated.
According to the NCI's Pluda, the cancer agency agreed to fund the Neovastat
trial at the urging of the National Center for Complementary and Alternative
Medicine, and because ``a lot of people out there are taking shark cartilage.''
A second shark compound undergoing testing is Magainin Pharmaceuticals'
squalamine, isolated from the tissues of the dog shark. Although squalamine has a
dramatic effect on tumors in mice, it has been less impressive in humans, failing to
help any of 16 patients in whom it was tested at Georgetown University in Washington.
