STANFORD UNIVERSITY MEDICAL CENTER
DEPARTMENT OF GENETICS

December 7, 1976

 

V
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t _ Dr. John Exied ~
pss Corporation
tanford Industrial Park NO
Palo Alto, California 94304 . s

Dear John,

I was interested and gratified to learn of the intense efforts you are
making to apply simplified mutagenicity assays to the evaluation of the
safety of Naproxen with respect to carcinogenesis.

These methods have been widely and properly acclaimed as offering a
substantial increase in sensitivity, as well as mitigation of cost and time,
over the whole animal methods generally used five years ago. The main use
of methods like the Ames test is to furnish a cheap and sensitive first filter
for screening suspect new compounds. For the categories of compounds like
alkylating agents, or substances that are metabolized into alkylating agents,
the test is probably far superior to animal testing - indeed is probably going
to produce a measure of false positives from the standpoint of practical public
health.

Unfortunately a certain number of carcinogenic substances like asbestos
and sex hormones operate by very different mechanisms and will not be picked
up by the Ames test. Plainly, animal tests must be continued for assaying such
compounds. In fact, I am rather deeply concerned that the rote way in which
animal testing is prescribed today makes them still quite inefficient for the
job they are called upon to do.

a

I have not really been able to take the time to go into a close analysis
of the Naproxen situation per se, and my remarks about the testing situation
generally come from a broad(but then somewhat distant) perspective rather than
from a close analysis of the data on the existing compounds. I have to say,
however, that I am not much persuaded that there is any logic to connect the
22-month chronic toxicity study requirement, with the need to look at carcinogenic
potential over still longer periods of time with larger numbers of animals. The
former battery of tests are evidently designed to be able to detect only the most
potent of carcinogens; and one can well argue that such agents are likely to be
picked up equally well either by the microbial assays or by other evidences of
cell-biological abnormalities. Compounds like anti-inflammatory agents that are
intended to be used chronically, over long periods of time, and in contexts
where there is some potentiality for patient abuse and imperfect medical super-—
vision would seem to me to warrant the most stringent long-term testing regardless
of the outcome either of the 22-month chronic toxicity, the microbial assays,
or one's favorable theoretical judgment based on the known biochemistry of the
compound. I was then both pleased to learn that you have tests of this kind in
progress and rather surprised and dismayed that the FDA had not required them
at the time of initial registration either of Naproxin or of the other anti-
inflammatory agents on the market at the present time. While there is nothing
in the information you gave me to suggest any other than a favorable outcome of

~2-
DEPARTMENT OF GENETICS, STANFORD UNIVERSITY SCHOOL OF MEDICINE, STANFORD, CALIFORNIA 94305 + (415) 497-3052
Dr. John Fried ~2— 12/7/76

such further rigorous testing, I would hope that this could become the
accepted standard, at least pending a further rationalization of cancer-
testing procedures.

While it has been some time since I terminated my long association with
the Molecular Biology Institute at Syntex, I recall those times with great

affection and it was a pleasure to renew these acquaintanceships.

Sincerely yours,

  
  

oshua Lederberg
Professor of Genetics

JL/rr