Syntex Conference, January 12-13, 1961

1. Discussion with Zaffaroni and Djerassi 1/12/61

Androgenic agents and alkalating agents are being used in combination in the
palliative therapy of breast cancer. The impression is that they are being used
simultaneously. However, there are some theoretical arguments that this is not
the best procedure and it would be preferable to use them in alternation with
one another. This would be on the same principle as the antagonism between
streptomycin and penicillin in antibacterial therapy since the androgen
presumably inhibits the rapid growth of the tumor cells. Such rapid growth in
turn is likely to be a necessary condition for the differential susceptability
of such cells to the carcinostatic agent. In fact, this would be a useful
experimental system for the purpose.

2. Query why dividing cells are in fact more susceptible to radiation and
chemical agents. Perhaps this can be attributed to the unique accessability

of single-stranded DNA to such agents. The DNA being in a single-strand stage
during some part of the division cycle. This in turn is something that can be
looked at directly and to some extent, has been, as a byproduct of work in
progress on the Subtilis transformation. At any rate, if this is the case, one
might use this approach to increase the selectivity of the inhibitory agents.
That is to say, those agents would be preferred that had the highest differential
in their rate of inactivation of double and of single-stranded DNA.

3. How to increase this differential in situ? At least one should inquire
whether one can take advantage of natural rhythms in the mitotic index in

order to identify specific times at which the greatest differential would be
likely as between various normal tissues of the host and the target tumor.

In addition, one might attempt to impose specific synchronization rhythms, for
example, by the alternate administration of androgenic and proslactogenic agents.
This again could be a specific subject for investigation, namely, to determine
the variation in sensitivity of such tumor cells depending on their hormonal
milfeu.

4. Context for discussion of these problems with Kaplan and with George Klein.