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New Study
Shows Effectivenss of Rubitecan
First,
the background:
“An essential component in a successful cancer treatment,”
says Dr. Beppino Giovanella, “is the balance between
the potency of the drug and the toxicity of the drug. Too
much toxicity causes unpleasant side, effects; too little
potency and the tumor remains untreated.”
Dr. Giovanella mobilized the staff at the Stehlin Laboratory
to conduct extensive toxicity tests on one of their promising
Camptotheca acuminata compounds.
“We have chosen to develop 9- Nitro-20(S)-Camptothecin
(Rubitecan),” explains Dr. Giovanella, “an insoluble
camptothecin which has demonstrated extraordinary anticancer
activity against human cancer.
”Next, the results:
Stehlin Foundation Director Bobby Anderson was astonished
at the initial results. “Dr. G. and the staff have experienced
enormous success with this schedule of oral testing. Out of
the 30 human tumors tested, all 30 stopped growing. And 24
of the 30 tumors were completely eradicated. All within low
levels of toxicity. This is world-class work.”
“Yes,” agreed Dr. Giovanella. “We are tremendously
excited.”
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| Chart
#1 shows two treatment schedules for 9NC. The black line
shows the rapid growth of an untreated tumor. The red
line shows the results of using 9NC against the tumor
on a schedule of 4 days on, 3 days off. The blue line
shows the same dosage of 9NC on a more aggressive schedule,
5 days on and 2 days off. |
| Chart #2 shows the powerful difference the correct dosage
can make. The black line represents the uncontrolled growth
of a pancreatic tumor. The red line indicates the presence
of a “too low” dosage of 9NC. The blue line
indicates the effectiveness of the appropriate dosage
of 9NC. “If a patient receives too little of the
treatment,” explains Stehlin Laboratory Supervisor
Dana Vardeman, “the patient's body builds up resistance
to the camptothecin and defeats the treatment. This can
be equated with the way we inoculate the body against
the flu with a very small amount of the flu virus. The
proper dosage makes a crucial difference in the patient's
healing.” |
Of mice
and men:
To determine the maximum tolerated dosage of 9-Nitro-20(S)-Camptothecin
(Rubitecan), Dr. Giovanella volunteered for the first human
test.
“I don’t want to administer to other people what
I am unwilling to take myself,” Dr. Giovanella explained.
Since the tests were for toxicity, someone without cancer
and with an understanding of clinical processes was ideal.
Dr. Giovanella obtained the permission of the St. Joseph Hospital
Medical Research Committee to be the human volunteer in the
toxicity tests.
Mice were the first step, though.
“The nude mice, developed here at Stehlin, are the best
testing and modeling system for human tumors,” says Giovanella.
“We xenografted 30 different tumors into the mice, and
began our dosage and toxicity tests.”
Varying dosages on sliding schedules were given to the nude
mice. Each mouse and each tumor was carefully monitored for
results. The 30 tumors comprised the most common human cancers:
lung, colorectal, breast, pancreatic, ovarian, prostate, stomach,
melanoma and leukemia. At this point, the 100% growth-rate
inhibition was observed in the tumors. Then, 24 of the 30
tumors completely disappeared from the host mice.
Animal testing with oral dosages (the insoluble form of the
drug) was the next important step in the development of an
effective human drug.
Finally, Dr. Giovanella began his toxicity tests by receiving
single oral doses of 9-NC at varying toxicity levels. After
a monitoring period of three months, repeated doses were administered
with a regimen of 4 days on and 3 days off. After no signs
of toxicity were observed in Dr. Giovanella’s blood levels,
the schedule was upped to 5 days on and 2 days off for 3 weeks.
No evident toxicity was found either clinically or through
blood analysis.
What’s next?
“From the data collected,” reports Dr. Giovanella,
“we find that 9-NC has a high potency against a wide
spectrum of human cancers. These cancers growing as xenografts
in nude mice are always growth inhibited and frequently destroyed
by the administration of non-toxic doses of 9-NC (Rubitecan).”
“Although sensitivity to 9-NC varies from tumor to tumor,”
adds Dana Vardeman, Laboratory Supervisor, “it is easy
to see that each and every tumor tested responded to the drug
at doses which were tolerated by the carrier animal.”
Vardeman helped conduct the tests along with Dr. Giovanella
and others at the Stehlin Foundation. “In mice, 9- NC
appears to be one of the most powerful and versatile anticancer
agents ever synthesized in a laboratory. Maintaining the anticancer
activity while administering it with low levels of toxicity
is the key to successful human treatment.”
Phase III trials involving Rubitecan and human patients with
pancreatic cancer have shown consistent positive results.
SuperGen continues to take Rubitecan (9-NC) through the regulatory
processes towards FDA approval. “
9-NC is going gang-busters against pancreatic cancer,”
says Dr. Giovanella. “And only human trials will be able
to demonstrate the full capabilities of 9-NC against all kinds
of human cancers. What this research is showing us is that
we are finding the schedules and dosage levels at which 9-NC
can inhibit and eradicate tumors while minimizing toxicities
for the people being treated.”
An abstract of these most recent findings is being published
in the International Journal of Oncology. Participating researchers
are: Beppino C. Giovanella, John S. Stehlin, Hellmuth R. Hinz,
Anthony J. Kozielski, Nicholas J. Harris and Dana M. Vardeman.
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